Bicyclic [5,6] imidazo pyrimodone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2

ABSTRACT

The present invention relates to bicyclic[ 5,6 ]imidazo pyrimidone compounds that inhibit Lp-PLA 2  activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA 2 , for example atherosclerosis, Alzheimer&#39;s disease. 
     In one aspect, this invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, 
                         
wherein different R groups are defined in the patent application.

RELATED APPLICATION

The present application claims priority from PCT InternationalApplication No. PCT/CN2013/070976 filed on Jan. 25, 2013 at the StateIntellectual Property Office of the People's Republic of China, theentire contents of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel bicyclic[5,6]imidazo pyrimidonecompounds, processes for their preparation, intermediates useful intheir preparation, pharmaceutical compositions containing them, andtheir use in therapy for the treatment of diseases or conditionsmediated by Lp-PLA₂.

BACKGROUND OF THE INVENTION

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) previously known asplatelet-activating factor acetylhydrolase (PAF-AH), is a phospholipaseA2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids.Lp-PLA₂ travels with low-density lipoprotein (LDL) and rapidly cleavesoxidized phosphatidylcholine molecules derived from the oxidation ofLDL. (See e.g., Zalewski A, et al., Arterioscler. Thromb. Vasc. Biol.,25, 5, 923-31 (2005)). Lp-PLA₂ hydrolyzes the sn-2 ester of the oxidizedphosphatidylcholines to give lipid mediators, lysophosphatidylcholine(lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has beenobserved that lysoPC and NEFAs elicit inflammatory responses. (See e.g.,Zalewski A, et al. (2005)).

A number of Lp-PLA₂ inhibitors and/or uses thereof have been previouslydescribed. (See. for example, published patent application nos.WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676,WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567,WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786,WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218,WO03/086400, WO03/87088, WO08/048,867, US 2008/0103156, US 2008/0090851,US 2008/0090852, and WO08/048,866.) Disclosed uses include treatingdisease that involves or is associated with endothelial dysfunction,disease that involves lipid oxidation in conjunction with Lp-PLA₂activity (e.g., associated with the formation of lysophosphatidylcholineand oxidized free fatty acids), and disease that involves activatedmonocytes, macrophages or lymphocytes or which is associated withincreased involvement of monocytes, macrophages or lymphocytes. Examplesof diseases or conditions include atherosclerosis (e.g. peripheralvascular atherosclerosis and cerebrovascular atherosclerosis), diabetes,hypertension, angina pectoris, after ischaemia and reperfusion,rheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, various neuropsychiatric disorders such asschizophrenia, myocardial infarction, ischaemia, reperfusion injury,sepsis, acute and chronic inflammation, and psoriasis.

Lp-PLA₂ inhibitors and/or uses thereof are also reported, for example,in PCT Publication Nos. WO05/003118 (and its Canadian family member CA2530816A1); WO06/063811; WO06/063813 and WO 2008/141176; JP 200188847;and US Published Patent Application Nos. US 2008/0279846 A1, US2010/0239565 A1, and US 2008/0280829 A1.

Other researchers have studied the effects related to Lp-PLA₂ andinhibitors thereof. For example, research data has also indicated thatLysoPC promotes atherosclerotic plaque development, which can ultimatelylead to the formation of a necrotic core. (See e.g., Wilensky et al.,Current Opinion in Lipidology, 20, 415-420 (2009)). In addition, theeffect of Lp-PLA₂ inhibitors on atherosclerotic plaque composition wasdemonstrated in a diabetic and hypercholesterolemic porcine model ofaccelerated coronary atherosclerosis. (See e.g., Wilensky et al., NatureMedicine, 10, 1015-1016 (2008)). These research results provided furtherevidence that Lp-PLA₂ inhibitors may be used to treat atherosclerosis.

Additional studies indicate that high Lp-PLA₂ activity is associatedwith high risk of dementia, including Alzheimer's disease (AD) (Seee.g., Van Oijen, et al. Annals of Neurology, 59, 139 (2006)). Higherlevels of oxidized LDL have also been observed in AD patients (See e.g.,Kassner et al. Current Alzheimer Research, 5, 358-366 (2008); Dildar, etal., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem, et al.Current Alzheimer Research, 7, 463-469 (2010)). Further, studies showthat neuroinflammation is present in AD patients and multiple cytotoxicinflammatory cytokines are up-regulated in AD patients. (See e.g.,Colangelo, et al., Journal of Neuroscience Research, 70, 462-473 (2002);Wyss-Coray, Nature Medicine, 12, September (2006)). Research has shownthat LysoPC function is a pro-inflammatory factor inducing multiplecytotoxic inflammatory cytokine release (See Shi, et al.Atherosclerosis, 191, 54-62 (2007)). Therefore, these studies provideadditional evidence that that the inhibitors of Lp-PLA₂ can be used totreat AD by inhibiting activity of Lp-PLA₂ and reducing lysoPCproduction.

In addition, use of an Lp-PLA₂ inhibitor in a diabetic andhypercholesterolemia swine model demonstrated that blood-brain-barrierleakage and brain amyloid beta protein (Aβ) burden, the pathologicalhallmarks of Alzheimer's disease, were reduced. (See U.S. PatentApplication Publication No. 2008/0279846). This publication describesseveral uses of Lp-PLA₂ inhibitors for treating diseases associated withblood-brain-barrier leakage, including, e.g., Alzheimer's disease andvascular dementia.

Further, neuroinflammation, including multiple cytotoxic cytokinerelease, is a common feature of all neurodegenerative diseases includingmultiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease,Alzheimer's disease, etc. (See e.g., Perry, Acta Neuropathol, 120,277-286 (2010)). As discussed above, Lp-PLA₂ inhibitors can reduceinflammation, for example, reducing multiple cytokine release bysuppressing lysoPC production. (See e.g., Shi, et al. Atherosclerosis191, 54-62 (2007)). Thus, inhibiting Lp-PLA₂ is a potential therapeutictreatment for neurodegenerative diseases including multiple sclerosis,amyotrophic lateral sclerosis, Parkinson's disease, etc.

In addition to the inflammatory effect, LysoPC has been implicated inleukocyte activation, induction of apoptosis and mediation ofendothelial dysfunction (See, e.g., Wilensky et al., Current Opinion inLipidology, 20, 415-420 (2009)). Therefore, it is believed that Lp-PLA₂inhibitors can be used to treat tissue damage associated with diabetesby reducing the production of lysoPC, which can cause a continuous cycleof vascular inflammation and increased reactive oxygen species (ROS)production. In light of the inflammatory roles of Lp-PLA₂ and theassociation between localized inflammatory processes and diabeticretinopathy, it is postulated that Lp-PLA₂ can be used to treat diabeticeye disease.

Glaucoma and age-related macular degeneration (AMD) are retinaneurodegenerative diseases. Studies suggest that inflammation, includingTNF-alpha signaling, may play an important role in the pathogenesis ofglaucoma and AMD (See e.g., Buschini et al., Progress in Neurobiology,95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173,ISSN0079-6123, Chapter 28). Thus, considering Lp-PLA₂ inhibitors'function of blocking inflammatory cytokine release (See e.g., Shi, etal. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA₂inhibitors can provide a potential therapeutic application for bothglaucoma and AMD.

In view of the number of pathological responses that are mediated byLp-PLA₂, attempts have been made to prepare compounds that inhibit itsactivity. Though a number of such compounds have been disclosed in theart, there remains a continuing need for inhibitors of Lp-PLA₂ which canbe used in the treatment of a variety of conditions.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to compounds of Formula (I)and pharmaceutically acceptable salts thereof,

-   -   R¹ and R² are independently CH₃ or H;    -   R³ is H, C₁₋₃ alkyl, cyclopropyl, or CD₃,    -   with the proviso that when R³ is H, CD₃, or C₁₋₃ alkyl, at least        one of R¹ or R² is CH₃;    -   each R⁵ is H or D;    -   A is (CH₂) or (CD₂)_(n), wherein n is 1 or 2; and    -   R⁴ is cyclopentyl or thiophenyl optionally substituted with one        or more Cl, or R⁴ is

-   -   wherein        -   R^(a) is H or F,        -   R^(b) is H, CN, or halo,        -   R^(c) is H, halo, or —O-A wherein A is phenyl, pyridinyl, or            pyrimidinyl, wherein phenyl, pyridinyl, or pyrimidinyl is            optionally substituted with one or two substituents            independently selected from the group consisting of CN, CF₃            and halo;        -   R^(d) is selected from the group consisting of F, H, CN and            CF₃, and        -   R^(e) is H or F.

This invention also relates to a pharmaceutical composition comprisingcompounds of this invention and one or more pharmaceutically acceptableexcipients.

The invention also relates to methods of treating a disease associatedwith the activity of Lp-PLA₂, which comprises treating a subject in needthereof with a therapeutically effective amount of an inhibitor ofLp-PLA₂. The disease may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidized free fatty acids; with lipidoxidation in conjunction with Lp-PLA₂ activity; or with endothelialdysfunction.

This invention also provides methods of treating a disease by inhibitingLp-PLA₂ activity. Exemplary diseases include, but are not limited to,neurodegeneration disease (e.g., Alzheimer's disease, vasculardementia), atherosclerosis, stroke, metabolic bone disorder (e.g., bonemarrow abnormalities), dyslipidemia, Paget's diseases, type II diseases,metabolic syndrome, insulin resistance, and hyperparathyroidism,diabetic ocular disorder (e.g., macular edema, diabetic retinopathy, andposterior uveitis), macular edema, wound healing, rheumatoid arthritis,chronic obstructive pulmonary disease (COPD), psoriasis, and multiplesclerosis.

The methods comprise administering a safe and effective amount of acompound of this invention to a subject in need thereof. It is notintended that the present invention is limited to any particular stageof the disease (e.g. early or advanced).

This invention also provides methods of treating Alzheimer's disease.The methods comprise administering to a subject in need thereof a safeand effective amount of a compound of this invention.

This invention also provides methods of treating atherosclerosis. Themethods comprise administering to a subject in need thereof a safe andeffective amount of a compound of this invention.

This invention also provides methods of decreasing beta amyloid (alsoreferred to as “Aβ”) accumulation in the brain of a subject. The methodscomprise administering to a subject in need thereof a safe and effectiveamount of a compound of the present invention. In certain embodiment,the beta amyloid is Abeta-42.

This invention also provides methods for treating eye diseases anddisorders by administering a compound of this invention. In certainembodiment, this invention provides methods of treating macular edema,which comprises administering to the subject a safe and effective amountof a compound of this invention. In certain embodiment, the macularedema is associated with diabetic eye disease, for example, diabeticretinopathy. In one embodiment, the macular edema is associated withposterior uveitis.

This invention also provides a use of compounds of this invention in themanufacture of a medicament for treating diseases described herein.

This invention also provides compounds of this invention for use in thetreatment described herein.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description of the embodiments of the invention and theappended claims, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. Also, as used herein, “and/or” refers to and encompasses anyand all possible combinations of one or more of the associated listeditems. It will be further understood that the terms “comprises” and/or“comprising,” when used in this specification, specify the presence ofstated features, integers, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, integers, steps, operations, elements, components,and/or groups thereof.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, biology and virology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. In the eventthat there is a plurality of definitions for a term used herein, thosein this section prevail unless stated otherwise.

All patents, patent applications and publications referred to herein areincorporated by reference in their entirety. In case of a conflict interminology, the present specification is controlling.

A. Definitions

As used herein, the term “disease” refers to any alteration in state ofthe body or of some of the organs, interrupting or disturbing theperformance of the functions and/or causing symptoms such as discomfort,dysfunction, distress, or even death to the person afflicted or those incontact with a person. A disease can also include a distemper, ailing,ailment, malady, disorder, sickness, illness, complain, interdispositionand/or affectation.

The term “neurodegeneration disease” as used herein refers to a variedassortment of central nervous system disorders characterized by gradualand progressive loss of neural tissue and/or neural tissue function. Aneurodegeneration disease is a class of neurological disorder or diseasewhere the neurological disease is characterized by a gradual andprogressive loss of neural tissue, and/or altered neurological function,typically reduced neurological function as a result of a gradual andprogressive loss of neural tissue. In some embodiments, theneurodegeneration diseases described herein are neurodegenerationdiseases or disorders where there is an abnormal blood brain barrier,for example a permeable blood brain barrier. Examples ofneurodegeneration diseases where there is a defective blood brainbarrier include, but are not limited to, Alzheimer's disease,Huntington's disease, Parkinson's disease, vascular dementia and thelike.

The term “vascular dementia” is also referred to as “multi-infarctdementia”, which refers to a group of syndromes caused by differentmechanisms, which all result in vascular lesions in the brain. The mainsubtypes of vascular dementia are, for example, vascular mild cognitiveimpairment, multi-infarct dementia, vascular dementia due to a strategicsingle infarct, (affecting the thalamus, the anterior cerebral artery,the parietal lobes or the cingulated gyrus), vascular dementia due tohemorrhagic lesions, small vessel disease (including, e.g. vasculardementia due to lacunar lesions and Binswanger disease), and mixedAlzheimer's Disease with vascular dementia.

The phrase “blood-brain barrier” or “BBB” are used interchangeablyherein, and are used to refer to the permeability barrier that exists inblood vessels as they travel through the brain tissue that severelyrestricts and closely regulates what is exchanged between the blood andthe brain tissue. The blood brain barrier components include theendothelial cells that form the innermost lining of all blood vessels,the tight junctions between adjacent endothelial cells that arestructural correlate of the BBB, the basement membrane of endothelialcells and the expanded foot process of nearby astrocytes which covernearly all of the exposed outer surface of the blood vessel.

The phrase “metabolic bone disease” as used herein refers to a variedassortment of bone diseases and disorders characterized by gradual andprogressive loss of bone tissue. Metabolic bone diseases describedherein are metabolic bone diseases whereby there is a condition ofdiffusely decreased bone density and/or diminished bone strength. Suchdiseases are characterized by histological appearance. Exemplarymetabolic bone diseases include, but are not limited to, osteoporosiswhich is characterized by decreased mineral and bone matrix, andosteomalacia which is characterized by decreased mineral but intact bonematrix.

The term “osteopenic diseases” or “osteopenia” are used interchangeablyherein, and refer to conditions with decreased calcification and/or bonedensity, and is a descriptive term used to refer to all skeletal systemsin which decreased calcification and/or bone density is observed.Osteopenia also refers to a reduced bone mass due to inadequate osteiodsynthesis.

The term “osteoporosis” refers to conditions in which mineral and/orbone matrix are decreased and/or bone mass is reduced.

“Alkyl” refers to a monovalent, saturated hydrocarbon chain having aspecified number of carbon atoms. For example, C₁₋₃ alkyl refers to analkyl group having from 1 to 3 carbon atoms. Alkyl groups may bestraight or branched. In some embodiments, branched alkyl groups mayhave one, two, or three branches. Exemplary alkyl groups include, butare not limited to, methyl, methylethyl, ethyl, propyl (n-propyl andisopropyl).

“Halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine(I). “Halo” refers to the halogen radicals: fluoro (—F), chloro (—Cl),bromo (—Br), or iodo (—I).

“Optionally substituted” indicates that a group, such as cyclopentyl,thiophenyl, phenyl, pyridinyl, or pyrimidinyl may be unsubstituted, orthe group may be substituted with one or more substituent as defined.

As used herein, “substituted” in reference to a group indicates that oneor more hydrogen atom attached to a member atom (e.g., carbon atom)within the group is replaced with a substituent selected from the groupof defined substituents. It should be understood that the term“substituted” includes the implicit provision that such substitution bein accordance with the permitted valence of the substituted atom and thesubstituent and that the substitution results in a stable compound (i.e.one that does not spontaneously undergo transformation such as byrearrangement, cyclization, or elimination and that is sufficientlyrobust to survive isolation from a reaction mixture). When it is statedthat a group may contain one or more substituent, one or more (asappropriate) member atom within the group may be substituted. Inaddition, a single member atom within the group may be substituted withmore than one substituent as long as such substitution is in accordancewith the permitted valence of the atom. Exemplary substituents include,but are not limited to, halo, hydroxyl, amino, amide, —SH, cyano, nitro,thioalkyl, carboxylic acid, —NH—C(═NH)—NH₂, alkyl, alkenyl, alkynyl,alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, in which alkyl,alkenyl, alkynyl, alkoxyl, aryl, heteroaryl, cycloalkyl, thioalkyl andheterocycloalkyl may be further substituted. Suitable substituents aredefined herein for each substituted or optionally substituted group.

As used herein, “treat”, “treating” or “treatment” in reference to acondition means: (1) to ameliorate the condition or one or more of thebiological manifestations of the condition, (2) to interfere with (a)one or more points in the biological cascade that leads to or isresponsible for the condition or (b) one or more of the biologicalmanifestations of the condition, (3) to alleviate one or more of thesymptoms or effects associated with the condition, and/or (4) to slowthe progression of the condition or one or more of the biologicalmanifestations of the condition.

As used herein, “subject” means a mammalian subject (e.g., dog, cat,horse, cow, sheep, goat, monkey, etc.), and particularly human subjectsincluding both male and female subjects, and including neonatal, infant,juvenile, adolescent, adult and geriatric subjects, and furtherincluding various races and ethnicities including, but not limited to,white, black, Asian, American Indian and Hispanic.

As used herein, “pharmaceutically-acceptable salts” refers to salts thatretain the desired biological activity of the subject compound andexhibit minimal undesired toxicological effects. Thesepharmaceutically-acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

As used herein, an “effective amount” means that the amount of acompound of this invention will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amount thatis effective to enhance normal physiological function.

B. Compounds

This invention provides, in a first aspect, compounds of Formula I andpharmaceutically acceptable salts thereof:

-   -   R¹ and R² are independently CH₃ or H;    -   R³ is H, C₁₋₃ alkyl, cyclopropyl, or CD₃,    -   with the proviso that when R³ is H, CD₃, or C₁₋₃ alkyl, at least        one of R¹ or R² is CH₃;    -   each R⁵ is H or D;    -   A is (CH₂) or (CD₂)_(n), wherein n is 1 or 2; and    -   R⁴ is cyclopentyl or thiophenyl optionally substituted with one        or more Cl, or R⁴ is

-   -   wherein        -   R^(a) is H or F,        -   R^(b) is H, CN, or halo,        -   R^(c) is H, halo, or —O-A wherein A is phenyl, pyridinyl, or            pyrimidinyl, wherein phenyl, pyridinyl, or pyrimidinyl is            optionally substituted with one or two substituents            independently selected from the group consisting of CN, CF₃            and halo;        -   R^(d) is selected from the group consisting of F, H, CN and            CF₃, and        -   R^(e) is H or F.

In one embodiment, this invention relates to compounds of Formula (I),wherein R¹ or R² is CH₃, or pharmaceutically acceptable salts thereof.In the other embodiment, this invention relates to compounds of Formula(I), wherein R¹ and R² are CH₃, or pharmaceutically acceptable saltsthereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R³ is CH₃ orpharmaceutically acceptable salts thereof. Yet, in one embodiment, thisinvention also relates to compounds of Formula (I) and any of the aboveapplicable embodiments, wherein R³ is isopropyl or pharmaceuticallyacceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein A is CH₂ and n is 1or pharmaceutically acceptable salts thereof. In one embodiment, thisinvention relates to compounds of Formula (I) and any of the aboveapplicable embodiments, wherein A is CD₂ and n is 1 or pharmaceuticallyacceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R⁵ is H orpharmaceutically acceptable salts thereof.

In one embodiment, this invention also relates to compounds of Formula(I) and any of the above applicable embodiments, wherein R⁴ is

wherein

R^(a) is H or F,

R^(b) is H, CN, or halo,

R^(c) is H, halo, or —O-A wherein A is phenyl, pyridinyl, orpyrimidinyl, wherein phenyl, pyridinyl, or pyrimidinyl is optionallysubstituted with one or two substituents independently selected from thegroup consisting of CN, CF₃ and halo;

R^(d) is selected from the group consisting of F, H, CN and CF₃, and

R^(e) is H or F,

or pharmaceutically acceptable salts thereof.

Yet, in one embodiment, this invention also relates to compounds ofFormula (I) and any of the above applicable embodiments, wherein R⁴ is

wherein

R^(a) is H,

R^(b) is F,

R^(c) is —O-A wherein A is pyridinyl or pyrimidinyl substituted with onesubstituent independently selected from the group consisting of F, C₁and CF₃,

R^(d) is H or F, and

R^(e) is H,

or pharmaceutically acceptable salts thereof.

In one embodiment, this invention also relates to compounds of Formula(I) and any of the above applicable embodiments, wherein R⁴ is

wherein

R^(a) is H or F,

R^(b) is H, CN or F,

R^(c) is F or H,

R^(d) is H or F, and

R^(e) is H, F, CN,

or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹, R² and R³ areCH₃ or pharmaceutically acceptable salts thereof. Yet, in oneembodiment, this invention also relates to compounds of Formula (I) andany of the above applicable embodiments, wherein R¹ or R² is CH₃, and R³is isopropyl or pharmaceutically acceptable salts thereof. Yet, in oneembodiment, this invention also relates to compounds of Formula (I) andany of the above applicable embodiments, wherein R¹ or R² is CH₃, and R³is CH₃ or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹ and R² are CH₃,R³ is CH₃ or isopropyl, R⁴ is cyclopentyl or thiophenyl optionallysubstituted with one or more Cl, or pharmaceutically acceptable saltsthereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹ and R² are CH₃,R³ is CH₃ or isopropyl, R⁴ is

wherein

R^(a) is H or F,

R^(b) is H, CN, or halo,

R^(c) is H or halo,

R^(d) is selected from the group consisting of F, H, CN and CF₃, and

R^(e) is H or F,

or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹ and R² are CH₃,R³ is CH₃ or isopropyl, R⁴ is

wherein

R^(a) is H or F,

R^(b) is H, CN, or halo,

R^(c) is H or halo,

R^(d) is —O-A wherein A is pyridinyl or pyrimidinyl substituted with onesubstituent selected from the group consisting of F, C₁ and CF₃, and

R^(e) is H or F,

or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹ and R² are CH₃,R³ is CH₃ or isopropyl, n is 1, R⁴ is phenyl substituted with two F andR⁵ is H, or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I)and any of the above applicable embodiments, wherein R¹ and R² are CH₃,R³ is isopropyl, n is 1, R⁴ is phenyl substituted with two F and R⁵ isH, or pharmaceutically acceptable salts thereof.

The compounds of Formula (I) or pharmaceutically acceptable saltsthereof may exist in stereoisomeric forms (e.g., it contains one or moreasymmetric carbon atoms). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The invention also covers the individual isomersof the compounds of Formula (I) or pharmaceutically acceptable saltsthereof as mixtures with isomers thereof in which one or more chiralcenters are inverted. Likewise, it is understood that the compounds ofFormula (I) or pharmaceutically acceptable salts thereof may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention. It is to beunderstood that the present invention includes all combinations andsubsets of the particular groups defined hereinabove. The scope of thepresent invention includes mixtures of stereoisomers as well as purifiedenantiomers or enantiomerically/diastereomerically enriched mixtures.Also included within the scope of the invention are individual isomersof the compounds of Formula (I) or pharmaceutically acceptable saltsthereof, as well as any wholly or partially equilibrated mixturesthereof. The present invention also includes the individual isomers ofthe compounds of Formula (I) or pharmaceutically acceptable saltsthereof as well as mixtures with isomers thereof in which one or morechiral centers are inverted. It is to be understood that the presentinvention includes all combinations and subsets of the particular groupsdefined hereinabove. The different isomeric forms may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

The invention also includes various deuterated forms of compounds ofFormula (I) or pharmaceutically acceptable salts thereof. Each availablehydrogen atom attached to a carbon atom may be independently replacedwith a deuterium atom. A person of ordinary skill in the art will knowhow to synthesize deuterated forms of compounds of Formula (I) orpharmaceutically acceptable salts thereof. Commercially availabledeuterated starting materials may be employed in the preparation ofdeuterated forms of compounds of Formula (I) or pharmaceuticallyacceptable salts thereof, or they may be synthesized using conventionaltechniques employing deuterated reagents (e.g. lithium aluminumdeuteride).

In addition to the free base form of the compounds described herein, thesalt form of the compounds is also within the scope of the presentinvention. The pharmaceutically-acceptable salts may be prepared in situduring the final isolation and purification of the compound, or byseparately reacting the purified compound in its free acid or free baseform with a suitable base or acid, respectively. For reviews on suitablepharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; PL Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; andBighley et al, Encyclopedia of Pharmaceutical Technology, Marcel DekkerInc, New York 1996, Volume 13, page 453-497.

In certain embodiments, compounds of the present invention may containan acidic functional group, which is acidic enough to form salts.Representative salts include pharmaceutically-acceptable metal saltssuch as sodium, potassium, lithium, calcium, magnesium, aluminum, andzinc salts; carbonates and bicarbonates of a pharmaceutically-acceptablemetal cation such as sodium, potassium, lithium, calcium, magnesium,aluminum, and zinc; pharmaceutically-acceptable organic primary,secondary, and tertiary amines including aliphatic amines, aromaticamines, aliphatic diamines, and hydroxy alkylamines such as methylamine,ethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine,diethanolamine, and cyclohexylamine.

In certain embodiments, compounds of the present invention may contain abasic group and are therefore capable of formingpharmaceutically-acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically-acceptableinorganic acids and pharmaceutically-acceptable organic acids. Thesesalts may be crystalline or amophorus. Exemplarypharmaceutically-acceptable acid addition salts include hydrochloride,hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate,phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate,isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate,malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate,lactate, heptanoate, phthalate, oxalate, succinate, benzoate,o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate,ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate,glutarate, glutamate, estolate, methanesulfonate (mesylate),ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate(besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), andnapthalene-2-sulfonate. In some embodiments, the pharmaceuticallyacceptable salts include the L-tartrate, ethanedisulfonate (edisylate),sulfate, phosphate, p-toluenesulfonate (tosylate), hydrochloride salt,methanesulfonate, citrate, fumarate, benzenesulfonate, maleate,hydrobromate, L-lactate, malonate, and S-camphor-10-sulfonate. Some ofthese salts form solvates, some are crystalline.

The compounds described herein, their pharmaceutically acceptable salts,or solvates or hydrates of either, may exist in one or more polymorphicform. Therefore, in a further aspect, the invention provides a polymorphof a compound defined herein or their pharmaceutically acceptable salts,or a polymorph of a solvate or hydrate of a compound described herein ora pharmaceutically acceptable salt thereof.

C. Synthesis of Compounds

The process to be utilized in the preparation of the compounds describedherein depends upon the desired compounds. Such factors as the selectionof the specific substituent and various possible locations of thespecific substituent all play a role in the path to be followed in thepreparation of the specific compounds of this invention. Those factorsare readily recognized by one of ordinary skill in the art.

In general, the compounds of the present invention may be prepared bystandard techniques known in the art and by known processes analogousthereto. General methods for preparing compounds of the presentinvention are set forth below. All starting material and reagentsdescribed in the below general experimental schemes are commerciallyavailable.

The skilled artisan will appreciate that if a substituent describedherein is not compatible with the synthetic methods described herein,the substituent may be protected with a suitable protecting group thatis stable to the reaction conditions. The protecting group may beremoved at a suitable point in the reaction sequence to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY(1999). In some instances, a substituent may be specifically selected tobe reactive under the reaction conditions used. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful as an intermediatecompound or is a desired substituent in a target compound.

R¹, R², R³, R⁴, R⁵ and A are as defined in Formula (I).

General Synthetic Scheme 1 provides an exemplary synthesis for compound6. The starting material or reagents for Scheme 1 are commerciallyavailable (for example TCI Shanghai Fine Chemicals) or are made fromcommercially available starting materials using methods known to thoseskilled in the art.

Step (i) may be carried out by reacting R₁R₂CHNH₂CH₂OH withtrichloropyrimidine using appropriate reagents such as triethylamine inan appropriate solvent such as acetonitrile under a suitable temperaturesuch as room temperature to provide compound 3.

Step (ii) is using appropriate reagents such as methanesulfonyl chloride(MsCl) and triethylamine (NEt₃) in a suitable solvent such asdichloromethane (DCM) at a suitable temperature such as roomtemperature.

Step (iii) may be taken place by reacting compound 3 with a suitablereagent such as potassium carbonate (K₂CO₃) at an appropriatetemperature such as 80° C.

Step (iv) may be carried out by reacting compound 4 with alkylatingreagents such as R₃—X (wherein X is halo) in the presence of a suitablebase such as potassium carbonate (K₂CO₃) under suitable solvent such asacetonitrile (ACN) at suitable temperature 90° C. to provide compound 5.

Step (v) may be carried out by reacting compound 5 with R₄-A-OH in thepresence of suitable base such as sodium hydride (NaH) in a suitablesolvent such as N,N-dimethylormamide (DMF) at suitable temperature suchas room temperature to provide compound 6.

All temperatures are reported in degrees Celsius. All otherabbreviations are as described in the ACS Style Guide (American ChemicalSociety, Washington, D.C., 1986).

LCMS Conditions:

1) Acidic Conditions:

Mobile phase: water containing 0.05% TFA/0.05% acetonitrile

Column: Agilent SB-C18 4.6×30 mm-1.8 microns

Detection: MS and photodiode array detector (PDA)

2) Basic Conditions:

Mobile phase: water containing 10 mmol NH₄HCO₃/acetonitrile

Column: XBridge™ C18 4.6×50 mm-3.5 microns

Detection: MS and photodiode array detector (PDA)

Mass Directed Autoprep Purification (MDAP) Conditions:

1) Acidic Conditions:

Instrument: Waters instrument

Column: Sunfire Prep C18 column (5 um, 19×50 mm)

Mobile phase: water containing 0.05% TFA/acetonitrile.

2) Basic Conditions:

Instrument: Waters instrument

Column: Xbridge Prep C18 column (5 um, 19×50 mm)

Mobile phase: water containing 0.04% ammonia/acetonitrile.

Abbreviations and Resource Sources

The following abbreviations and resources are used herein below:

ISCO system—Teledyne ISCO(http://www.isco.com/html/seFlashChromatography.html)

r.t/rt/RT—room temperature

ACN—acetonitrile

Aq.—aqueous

CDI—1,1′-carbonyldiimidazole

CV—Column volumes

DCM—dichloromethane

DMAP—4-dimethylaminopyridine

DMF—dimethylformamide

DMSO—dimethyl sulfoxide

EA—ethyl acetate

FC—flash chromatography

TFA—trifluoro acetic acid

THF—tetrahydrofuran

PE—petroleum ether

EXAMPLES

The following synthetic processes and examples are provided to morespecifically illustrate the invention. These examples are not intendedto limit the scope of the invention, but rather to provide guidance tothe skilled artisan to prepare and use the compounds, compositions, andmethods of the invention. While particular embodiments of the inventionare described, the skilled artisan will appreciate that various changesand modifications can be made without departing from the spirit andscope of the invention.

D1 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol

To a mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) andtriethylamine (11 mL, 82 mmol) in acetonitrile (20 mL) was slowly addeda solution of 2-(methylamino)propan-1-ol (2.9 g, 33 mmol) inN,N-dimethylformamide (DMF) (2 mL) at 0° C. The reaction mixture wasstirred at same temperature for 1 h, then filtered through a thin pad ofcelite and concentrated. Purification via silica gel flashchromatography (petroleum ether/ethyl acetate=4/1˜1/1) afforded thetitle product as an oil.

LC-MS (ESI): m/z 236[M+H]⁺; 1.09 min (ret time).

D2 4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one

To a mixture of 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol(3.0 g, 13 mmol) and LiOH one hydrate (1.60 g, 38 mmol) in water (2 mL)was added H₂O₂ (0.78 mL, 25 mmol). The reaction mixture was stirred at45° C. for 3 h, then quenched with Na₂S₃O₃ solution (2 mL) andconcentrated. Purification via Biotage Spla HPFC system (C18, mobilephase: 0.01% NH₄HCO₃ in H₂O/CH₃CN, 10˜95%, 9.5 min, 30 mL/min) affordedthe title product as a white solid.

LC-MS (ESI): m/z 218 [M+H]⁺; 0.73 min (ret time).

D3 2-((6-chloro-2-oxo-2,3-dihydropyrimidin-4-yl)(methyl)amino)propylmethanesulfonate

To a mixture of4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (1.0g, 4.6 mmol) and triethylamine (1.9 mL, 14 mmol) in tetrahydrofuran(THF) (15 mL) was added MsCl (0.72 mL, 9.2 mmol) at 0˜5° C. The reactionmixture was stirred at room temperature overnight, and then quenchedwith 1 M NaHCO₃ solution, diluted with water and extracted with ethylacetate. Combined organic parts were dried over anhydrous Na₂SO₄,filtered and concentrated to give the residue as yellow oil. The crudewas used into next step without further purification.

LC-MS (ESI): m/z 296[M+H]⁺; 1.04 min (ret time).

D4 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

A mixture of2-((6-chloro-2-oxo-2,3-dihydropyrimidin-4-yl)(methyl)amino)propylmethanesulfonate (800 mg, 2.71 mmol) and K₂CO₃ (748 mg, 5.41 mmol) inacetonitrile (6 mL) was stirred at 80° C. for 3 h, cooled to roomtemperature and concentrated. Purification via Biotage Spla HPFC system(C18, mobile phase: 0.01% NH₄HCO₃/H₂O, 10˜95% CH₃CN, 9.5 min, 30 mL/min)afforded the title product as an orange solid.

LC-MS (ESI): m/z 200 [M+H]⁺; 0.77 min (ret time).

D5 2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-formylbenzonitrile

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3-fluoro-5-(trifluoromethyl)phenol and2-fluoro-5-formylbenzonitrile.

LC-MS (ESI): m/z 308 [M−H]⁻; 1.78 min (ret time).

D6 2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D31 starting from2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-formylbenzonitrile.

LC-MS (ESI): m/z 294 [M−H₂O+H]⁺; 1.71 min (ret time).

D7 (3,4-difluorophenyl)methanol

To a solution of 3,4-difluorobenzaldehyde (200 mg, 1.41 mmol) inmethanol (4 mL) was added NaBH₄ (80 mg, 2.1 mmol). The reaction mixturewas stirred at rt for 10 min., then diluted with water and extractedwith ethyl acetate. The organic part was separated, washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The crude wasused into next step without further purification.

LCMS (ESI): m/z 308 [M+H]⁺; 2.03 min (ret time)

D8 4-(2-fluoro-4-formylphenoxy)-2-(trifluoromethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and4-hydroxy-2-(trifluoromethyl)-benzonitrile.

LC-MS (ESI): m/z 308 [M−H]⁻; 1.40 min (ret time).

D9 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D31 starting from4-(2-fluoro-4-formylphenoxy)-2-(trifluoromethyl)benzonitrile.

LC-MS (ESI): m/z 310 [M−H]⁻; 1.30 min (ret time).

D10 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol

To a solution of 2,4,6-trichloropyrimidine (20.0 g, 109 mmol) inacetonitrile (500 mL) was added triethylamine (11.03 g, 109 mmol) at 0°C. After 5 min at room temperature, 2-amino-2-methylpropan-1-ol (9.72 g,109 mmol) was added portionwise. The reaction mixture was stirred foranother 1 h at room temperature, filtered and concentrated. Purificationvia silica gel column (ethyl acetate/petroleum ether=1/10 to 1/1)afforded the title product.

LC-MS (ESI): m/z 236 [M+H]⁺; 1.11 min (ret time)

D11 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropylmethanesulfonate

To a solution of2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol (6.67 g, 28.3mmol) and triethylamine (11.59 mL, 85 mmol) in dichloromethane (DCM)(100 mL) was added dropwise MsCl (4.40 mL, 56.5 mmol) at 0° C. Thereaction mixture was stirred at rt for 2 h, diluted with DCM (100 mL),washed with water (50 mL×3) then brine (50 mL×2), dried over Na₂SO₄,filtered and concentrated to give the residue as a yellow solid, whichwas used for the next step without further purification.

LC-MS (ESI): m/z 314 [M+H]⁺; 1.04 min (ret time)

D12 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropylmethanesulfonate (3.00 g, 9.55 mmol) in 1,4-dioxane (15 mL) and water(15 mL) was added potassium carbonate (4.62 g, 33.4 mmol). The reactionmixture was stirred at 80° C. for 2 h, filtered, extracted with ethylacetate (5 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give the crude product, which was used into next step without furtherpurification.

LC-MS (ESI): m/z 200 [M+H]⁺; 0.73 min (ret time)

D13 (2,4-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from 2,4-difluorobenzaldehyde.

LC-MS (ESI): m/z 127 [M−H₂O+H]⁺; 1.93 min (ret time).

D14 3-fluoro-4-((6-(trifluoromethyl)-3-pyridinyl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 6-(trifluoromethyl)-3-pyridinol and3,4-difluorobenzaldehyde.

LC-MS (ESI): m/z 286[M+H]⁺, 3.20 min (ret time).

D15 (3-fluoro-4-((6-(trifluoromethyl)-3-pyridinyl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((6-(trifluoromethyl)-3-pyridinyl)oxy)benzaldehyde.

LC-MS (ESI): m/z 288[M+H]⁺, 2.88 min (ret time).

D16 7-chloro-1,2,2-trimethyl-2,3-dihydromidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (500mg, 2.505 mmol) and dimethyl carbonate (0.422 ml, 5.01 mmol) inN,N-dimethylf-ormamide (DMF) (16 ml) was added K₂CO₃ (346 mg, 2.51mmol). The reaction mixture was sealed in a microwave and irradiatedwith a microwave using initial normal to 140° C. for 1 h. Purificationvia reverse phase chromarography (water/acetonitrile, 0.05% TFA inwater) afforded the title product as a brown solid.

LC-MS (ESI): m/z 214 [M+H]⁺; 1.25 min (ret time)

D17 (S)-2-aminopropan-1-ol

To a suspension of LiAlH₄ (20.5 g, 539 mmol) in dry THF (80 mL) wasadded dropwise a solution of (S)-2-aminopropanoic acid (12.0 g, 135mmol) in THF (120 mL) at 0° C. The reaction mixture was stirred at 0° C.for 30 min, then room temperature for 3 h and refluxed for 9 h. Thereaction mixture was cooled to 0° C., then diluted with 15% NaOHsolution (25 mL), stirred at room temperature for 2 h and filtered. Thefiltrate was dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude was used into next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ: 3.49 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H),2.42 (s, 3H), 0.99 (d, J=6.4 Hz, 3H).

D18 (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propan-1-ol

To a solution of 2,4,6-trichloropyrimidine (4.70 g, 25.6 mmol) andtriethylamine (7.78 g, 77.0 mmol) in acetonitrile (150 mL) was added asolution of (S)-2-aminopropan-1-ol (2.31 g, 30.7 mmol) in acetonitrile(150 mL) at 0° C. The reaction mixture was allowed to room temperatureand stirred for 12 h, then filtered and concentrated. Purification viacolumn chromatography (elutriant: petroleum ether/ethyl acetate=4/1)afforded the title product.

LC-MS (ESI): m/z 222 [M+H]⁺; 0.86 min (ret time).

D19 (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propyl methanesulfonate

To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propan-1-ol(2.10 g, 9.46 mmol), MsCl (1.19 g, 10.4 mmol) and triethylamine (2.87 g,28.4 mmol) in tetrahydro-furan (THF) (60 mL) was added dropwisemethanesulfonyl chloride (1.19 g, 10.4 mmol) at 0° C. The reactionmixture was stirred at room temperature for 16 h, then filtered andconcentrated. The crude was used into next step without furtherpurification.

LC-MS (ESI): m/z 300 [M+H]⁺; 1.029 (ret time).

D20 (S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propylmethanesulfonate (1.86 g, 6.20 mmol) and potassium carbonate (2.57 g,18.6 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reactionmixture was stirred at 100° C. for 2 h, then concentrated to removesolvent, diluted with water (20 mL), stirred at room temperature for 10min and filtered. The filter cake was recrystallized with DCM (30 mL) togive the title product.

LC-MS (ESI): m/z 186 [M+H]⁺; 0.41 min (ret time).

D21 2-(trifluoromethyl)-4H-pyran-4-one

To a mixture of KO^(t)Bu (729 mg, 6.49 mmol) in diethyl ether (10 mL) at5° C. were added methyl 2,2,2-trifluoroacetate (767 mg, 5.99 mmol) and(E)-4-methoxybut-3-en-2-one (500 mg, 4.99 mmol). The reaction mixturewas stirred at rt for 3 h, then quenched with water and extracted withether. Combined organic parts were dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in isopropanol (150 mL) and 35%solution of hydrochloric acid (0.5 mL) and refluxed for 45 min. Then thesolution was concentrated to remove alcohol and fractionated at reducedpressure to get the title product as yellow oil.

LC-MS (ESI): m/z 165 [M+H]⁺; 1.30 min (ret time).

D22 2-(trifluoromethyl)pyridin-4-ol

To a solution of 2-(trifluoromethyl)-4H-pyran-4-one (350 mg, 2.13 mmol)in MeOH (15 mL) was added ammonium hydroxide (14.8 mL, 107 mmol) at 25°C. The reaction mixture was stirred at 90° C. for 10 h, thenconcentrated, diluted with water and extracted with ethyl acetate.Combined organic parts were dried over Na₂SO₄, filtered and con.Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01%NH₄HCO₃, CH₃CN/water, 10˜95%, 9.5 min, 30 mL/min) afforded the titleproduct (280 mg) as a yellow solid.

LC-MS (ESI): m/z 164 [M+H]⁺; 1.30 min (ret time).

D23 3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and2-(trifluoromethyl)pyridin-4-ol.

LC-MS (ESI): m/z 286 [M+H]⁺; 1.65 min (ret time).

D24 (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 288 [M+H]⁺; 1.62 min (ret time).

D25 (S)-2-formamidopropanoic acid

To a solution of (S)-2-aminopropanoic acid (27 g, 303 mmol) in formicacid (80%, 115 mL) was added dropwise acetic anhydride (70 mL) at 0° C.The reaction mixture was stirred at 0° C. for 10 min, then roomtemperature for 4 h, diluted with water (70 mL) and concentrated toremove solvent. Recrystallization with water afforded the title product.

¹H NMR (400 MHz, DMSO-d6) δ: 8.34 (br, 1H), 7.96 (s, 1H), 4.24 (m, 1H),1.25 (d, J=4.4 Hz, 3H)

D26 (S)-2-(methylamino)propan-1-ol

To a suspension of LiAlH₄ (2.59 g, 68.3 mmol) in dry THF (80 mL) wasadded dropwise a solution of (S)-2-formamidopropanoic acid (2.00 g, 17.1mmol) in THF (120 mL) at 0° C. The reaction mixture was stirred at 0° C.for 30 min then rt for 3 h and reflux for 9 h. The mixture was cooled at0° C. and 15% NaOH solution (5 mL) was slowly added. The reactionmixture was stirred at rt for 2 h, filtered, dried over Na₂SO₄,concentrated. The crude product was used into next step without furtherpurification.

¹H NMR (400 MHz, CDCl₃): δ: 3.61 (m, 1H), 3.27 (m, 1H), 2.67 (m, 1H),2.42 (s, 3H), 1.04 (d, J=7.6 Hz, 3H).

D27 (S)-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol

To a solution of 2,4,6-trichloropyrimidine (5.42 mL, 47.1 mmol) andtriethylamine (19.7 mL, 141 mmol) in acetonitrile (40 mL) was slowlyadded (S)-2-(methylamino)propan-1-ol (6.30 g, 70.7 mmol) inN,N-dimethylformamide (DMF) (3.00 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h, filtered, dried over anhydrous Na₂SO₄,concentrated. Purification via flash chromatography column (petroleumether/ethyl acetate=10/1) afforded the title product.

¹H NMR (400 MHz, CDCl₃): δ: 6.37 (br, 1H), 3.71 (m, 2H), 2.93 (br, 3H),2.03 (br, 1H), 1.18 (d, J=6.8 Hz, 3H).

D28(S)-4-chloro-6-((1-hydroxypropan-2-yl(methyl)amino)pyrimidin-2(1H)-one

To a mixture of(S)-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol (3.80 g,16.1 mmol) and lithium hydroxide one hydrate (2.03 g, 48.3 mmol) inwater (5 mL) was added hydrogen peroxide (3.29 mL, 32.2 mmol). Thereaction mixture was stirred at 45° C. for 3 h, diluted with water (30mL) and extracted with ethyl acetate (20 mL×3). Combined organic partswere dried over Na₂SO₄, filtered and concentrated. The crude was usedinto next step without purification.

LC-MS (ESI): m/z 218 [M+H]⁺; 0.63 min (ret time).

D29(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of(S)-4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one(700 mg, 3.22 mmol) and triethylamine (1.35 mL, 9.65 mmol) intetrahydrofuran (THF) (20 mL) was added methanesulfonyl chloride (0.508mL, 6.43 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h and concentrated. Purification via Prep-HPLC(column: YMC-Actus Triart C18 150×30 mm; 2 M NH₃ in methanol) affordedthe title product.

LC-MS (ESI): m/z 200 [M+H]⁺; 0.34 min (ret time).

D30 4-((6-chloropyridin-3-yl)oxy)-3-fluorobenzaldehyde

A mixture of 3,4-difluorobenzaldehyde (2.00 g, 14.8 mmol),6-chloropyridin-3-ol (1.82 g, 14.1 mmol) and potassium carbonate (2.14g, 15.5 mmol) in N,N-dimethylformamide (DMF) (25 mL) was stirred at 110°C. for 12 h, diluted with ethyl acetate (50 mL), washed with water (50mL×2). The organic part was separated, dried over anhydrous Na₂SO₄,filtered and concentrated. Purification via silica gel (3% ethyl acetatein petroleum ether) afforded the title product (2.8 g)

LCMS (ESI): m/z 252 [M+H]⁺; 0.80 min (ret time)

D31 (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol

To a solution of 4-((6-chloropyridin-3-yl)oxy)-3-fluorobenzaldehyde(2.80 g, 11.1 mmol) in methanol (25 mL) was added portionwise solidNaBH₄ (0.842 g, 22.3 mmol) at room temperature. The reaction mixture wasstirred at 25° C. for 2 h, concentrated to remove solvent, dissolved inwater (50 mL) and extracted with ethyl acetate (50 mL×2). Combinedorganic parts were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was used into next step withoutpurification (2.8 g).

LCMS (ESI): m/z 254 [M+H]⁺; 0.74 min (ret time)

D32 4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and 6-chloropyridin-3-ol.

LCMS (ESI): m/z 252 [M+H]⁺; 0.80 min (ret time)

D33 (4-((6-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzaldehyde.

LCMS (ESI): m/z 272 [M+H]⁺; 0.75 min (ret time)

D34 Dideutero(2,3-difluorophenyl)methanol

To a solution of 2,3-difluorobenzoic acid (5.00 g, 31.6 mmol) intetrahydrofuran (THF) (80 mL) in ice bath was added lithium aluminiumdeuteride (1.00 g, 23.8 mmol). The reaction mixture was graduallyallowed to rt and stirred for two days, then diluted with ethyl acetate(150 mL) and water (5 mL), mixed with anhydrous Na₂SO₄, filtered andconcentrated. Purification via ISCO system (ethyl acetate/petroleumether) afforded the title product as colorless oil.

LCMS (ESI): m/z 129 [M−H₂O+H]⁺; 2.07 min (ret time).

D35(S)-7-chloro-1-isopropyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a mixture of(S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50mg, 0.27 mmol) and 2-iodopropane (68.7 mg, 0.404 mmol) in acetonitrile(1 mL) was added Cs₂CO₃ (176 mg, 0.539 mmol). The reaction mixture wasstirred at 90° C. for 1 h, then cooled to room temperature, filtered andconcentrated to give the residue as a brown solid. The crude was usedinto next step without purification.

LCMS (ESI): m/z 228 [M+H]⁺; 1.58 min (ret time)

D367-chloro-1-trideuteromethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a mixture of7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50mg, 0.25 mmol) and TsOCD₃ (114 mg, 0.301 mmol) in acetonitrile (2 mL)was added Cs₂CO₃ (163 mg, 0.501 mmol). The reaction mixture was stirredat rt for 1 h, filtered and concentrated to give the residue as a brownsolid. The crude was used into next step without purification.

D37 N-(2-bromoethyl)-2,6-dichloropyrimidin-4-amine

To a solution of 2,4,6-trichloropyrimidine (10 g, 54.5 mmol) andtriethylamine (11.0 g, 109 mmol) in acetonitrile (15 ml) was addeddropwise triethylamine (0.552 g, 5.45 mmol). The mixture was stirred for3 h, diluted with water (40 mL) and extracted with ethyl acetate (20mL×2). Combined organic parts were washed with brine (30 mL×2), driedover Na₂SO₄ and concentrated. The crude product (10 g) was directly usedinto next step without further purification.

LC-MS (ESI): m/z 270 [M+H]⁺; 1.44 min (ret time)

D38 7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a mixture of N-(2-bromoethyl)-2,6-dichloropyrimidin-4-amine (10 g, 18mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was added K₂CO₃ (4.85g, 35.1 mmol). The reaction mixture was stirred at 70° C. for 4 h, thendirectly used into next step without workup and purification.

LC-MS (ESI): m/z 172 [M+H]⁺; 0.51 min (ret time)

D39tert-butyl-7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate

To the above mixture was added Boc₂O (1.999 g, 11.65 mmol) and DMAP(0.142 g, 1.17 mmol). The reaction mixture was stirred at rt for 3 h,diluted with brine (30 mL) and extracted with ethyl acetate (20 mL×2).Combined organic parts were washed with brine (20 mL×2), dried overanhydrous Na₂SO₄ and concentrated. Purification via column on silica gel(eluent: ethylacetate) afforded the title product (1.5 g) as a whitesolid.

LC-MS (ESI): m/z 272 [M+H]⁺; 1.24 min (ret time)

D40 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

A mixture of 7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (300mg, 1.75 mmol), cyclopropylboronic acid (300 mg, 3.50 mmol),4,4′-bipyridine (273 mg, 1.75 mmol), copper (I) acetate (214 mg, 1.75mmol) and Na₂CO₃ (371 mg, 3.50 mmol) in 1,2-dichloroethane (DCE) (20 mL)was stirred at 70° C. for 3 h and concentrated to remove solvent undervacuo. Purification via Biotage system with inverse phase column (waterand acetonitrile as eluent) afforded the title product (200 mg).

LC-MS (ESI): m/z 212 [M+H]⁺; 1.20 min (ret time)

D41 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 2-(trifluoromethyl)pyridin-4-ol and3,4,5-trifluorobenzaldehyde.

LC-MS (ESI): m/z 304 [M+H]⁺; 1.17 min (ret time).

D42(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 306 [M+H]⁺; 1.07 min (ret time).

D43 4-((5-chloropyridin-3-yl)oxy)-3,5-difluorobenzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4,5-trifluorobenzaldehyde and5-chloropyridin-3-ol.

LCMS (ESI): m/z 270 [M+H]⁺; 0.78 min (ret time).

D44 (4-((5-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from4-((5-chloropyridin-3-yl)oxy)-3,5-difluorobenzaldehyde.

LCMS (ESI): m/z 272 [M+H]⁺; 0.72 min (ret time)

D45 3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and5-(trifluoromethyl)pyridin-3-ol.

D46 (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 288 [M+H]⁺; 0.77 min (ret time).

D47 3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 2-fluoropyridin-4-ol and 3,4-difluorobenzaldehyde.

LC-MS (ESI): m/z 236 [M+H]⁺; 0.74 min (ret time).

D48 (3-fluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((2-fluoropyridin-4-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 272 [M+H]⁺; 1.08 min (ret time).

D49 4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4,5-trifluorobenzaldehyde and2-chloropyridin-4-ol.

LC-MS (ESI): m/z 270 [M+H]⁺; 0.79 min (ret time).

D50 (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzaldehyde.

D51 2-fluoro-5-(hydroxymethyl)benzonitrile

To a solution of 3-cyano-4-fluorobenzoic acid (1.00 g, 6.06 mmol) intetrahydrofuran (THF) (20 mL) was added dropwise CDI (1.47 g, 9.08 mmol)at 0° C. After at room temperature for 30 min, sodium borohydride (0.687g, 18.2 mmol) was added dropwise at 0° C. The reaction mixture wasstirred at room temperature for 16 h, quenched with saturated aqueousNH₄Cl and extracted with ethyl acetate. The organic part was separated,dried over Na₂SO₄, filtered and concentrated. Purification via flashcolumn (petroleum ether/ethyl acetate=10/1) afforded the title product(350 mg).

LC-MS (ESI): m/z 152 [M+H]⁺; 0.52 min (ret time).

D52 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5-ol

A solution of 1,3-diaminopropan-2-ol (10.0 g, 111 mmol) and ethyl2,2,2-trifluoroacetate (15.8 g, 111 mmol) in p-xylene (150 mL) wasstirred at 160° C. for 4 h, then concentrated to remove solvent underreduced pressure to afford the crude product as an oil, which was usedinto next step without purification.

LC-MS (ESI): m/z 169 [M+H]⁺; 0.85 min (ret time).

D53 3-fluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and2-(trifluoromethyl)pyrimidin-5-ol.

LC-MS (ESI): m/z 287 [M+H]⁺; 1.17 min (ret time).

D54 (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 289 [M+H]⁺; 1.11 min (ret time).

D557-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol (3.40 g, 14.4mmol) and triethylamine (11.8 mL, 86.4 mmol) in dichloromethane (DCM)(40 mL) was added dropwise MsCl (4.48 mL, 57.6 mmol) at 0° C. Thereaction mixture was stirred at rt for 2 h, then diluted with DCM (40mL), washed with water (30 mL×3) then brine (30 mL×2), dried overNa₂SO₄, filtered and concentrated. Purification via MDAP (column: Luna250×50 mm×10 um; MeCN, 0.2% water, 0.2% Formic acid) afforded the titleproduct (850 mg) as a yellow solid.

LC-MS (ESI): m/z 278 [M+H]⁺; 0.71 min (ret time).

D56 3-(benzyloxy)-5-(trifluoromethyl)pyridine

To a solution of 3-chloro-5-(trifluoromethyl)pyridine (10.0 g, 55.1mmol) in N,N-dimethylformamide (DMF) (150 mL) was added dropwisephenylmethanol (5.96 g, 55.1 mmol) under nitrogen at rt. The reactionmixture was stirred at 40° C. for 2 h, diluted with water (300 mL) andextracted with ethyl acetate (300 mL×3). Combined organic parts werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Thecrude product (100 g) was used into next step without furtherpurification.

LC-MS (ESI): m/z 254 [M+H]⁺; 0.86 min (ret time).

D57 5-(trifluoromethyl)pyridin-3-ol

To a solution of 3-(benzyloxy)-5-(trifluoromethyl)pyridine (10 g, 39.5mmol) in methanol (100 mL) was added Pd/C (0.500 g, 4.70 mmol). Thereaction mixture was stirred at 50° C. under H₂ (55 psi) for 24 h,filtered and concentrated under reduce pressure to afford the crudeproduct (2.5 g).

LC-MS (ESI): m/z 164 [M+H]⁺; 0.51 min (ret time).

D58 3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 5-(trifluoromethyl)pyridin-3-ol and3,4,5-trifluorobenzaldehyde

LC-MS (ESI): m/z 304 [M+H]⁺; 0.83 min (ret time).

D59(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 306 [M+H]⁺; 0.79 min (ret time).

D60 3,5-difluoro-4-((6-fluoropyridin-3-yloxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4,5-trifluorobenzaldehyde and6-fluoropyridin-3-ol.

LC-MS (ESI): m/z 254 [M+H]⁺; 1.13 min (ret time).

D61 (3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 256 [M+H]⁺; 1.04 min (ret time).

D62 4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and 2-chloropyridin-4-ol.

LC-MS (ESI): m/z 252 [M+H]⁺; 0.76 min (ret time).

D63 (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzaldehyde.

LC-MS (ESI): m/z 254 [M+H]⁺; 1.04 min (ret time).

D647-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (100mg, 0.501 mmol) and iodoethane (94.0 mg, 0.601 mmol) in acetonitrile (4mL) was added Cs₂CO₃ (326 mg, 1.00 mmol). The reaction mixture wasstirred at 90° C. for 1 h, filtered and concentrated to afford the crudeproduct (110 mg) as a brown solid.

LCMS (ESI): 228 [M+H]⁺; 1.52 min (ret time)

D65 (2,3-difluorophenyl)methanol dideuteride

The title compound was prepared by a procedure similar to that describedfor D34 starting from 2,3-difluorobenzoic acid.

LCMS (ESI): 129 [M−H₂O+H]⁺; 1.96 min (ret time)

D66 Dideutero(2,4,5-trifluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D34 starting from 2,4,5-trifluorobenzoic acid.

LC-MS (ESI): m/z 147 [M+H]⁺; 2.15 min (ret time).

D67(S)-7-chloro-1-ethyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of(S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50.0mg, 0.269 mmol) and iodoethane (63.0 mg, 0.404 mmol) in acetonitrile (1ml) was added Cs₂CO₃ (176 mg, 0.539 mmol). The reaction mixture wasstirred at 90° C. for 1 h, filtered and concentrated to give crudeproduct (80 mg) as a brown solid.

LCMS (ESI): m/z 214[M+H]⁺; 1.38 min (ret time)

D68 3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and 6-fluoropyridin-3-ol.

LCMS (ESI): m/z 236 [M+H]⁺; 1.09 min (ret time)

D69 (3-fluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzaldehyde.

LCMS (ESI): m/z 238 [M+H]⁺; 1.02 min (ret time)

D707-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (400mg, 2.00 mmol) and 2-iodopropane (375 mg, 2.20 mmol) in acetonitrile (7mL) was added Cs₂CO₃ (1.31 g, 4.01 mmol). The reaction mixture wasstirred at 90° C. for 2 h, filtered and concentrated. Purification viaMDAP afforded the title product (40 mg) as a white solid.

LCMS (ESI): m/z 242 [M+H]⁺; 1.77 min (ret time).

D71 (R)-2-formamidopropanoic acid

The title compound was prepared by a procedure similar to that describedfor D25 starting from (R)-2-aminopropanoic acid.

¹H NMR (400 MHz, CDCl₃) δ: 8.62 (s, 1H), 8.11 (br, 1H), 5.05 (m, 1H),1.92 (m, 3H).

D72 (R)-2-(methylamino)propan-1-ol

The title compound was prepared by a procedure similar to that describedfor D26 starting from (R)-2-formamidopropanoic acid.

¹H NMR (400 MHz, CDCl₃): δ: 3.60 (m, 1H), 3.28 (m, 1H), 2.65 (m, 1H),2.42 (s, 3H), 1.05 (d, J=7.2 Hz, 3H).

D73 (R)-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol

The title compound was prepared by a procedure similar to that describedfor D27 starting from 2,4,6-trichloropyrimidine and(S)-2-(methylamino)propan-1-ol.

LC-MS (ESI): m/z 236 [M+H]⁺; 0.85 min (ret time).

D74(R)-4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one

The title compound was prepared by a procedure similar to that describedfor D28 starting from(R)-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol.

LC-MS (ESI): m/z 218 [M+H]⁺; 0.65 min (ret time).

D75(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor D29 starting from(R)-4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one.

LC-MS (ESI): m/z 200 [M+H]⁺; 0.61 min (ret time).

D76 3-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D30 starting from 3,4-difluorobenzaldehyde and3-fluoro-5-(trifluoromethyl)phenol.

LCMS (ESI): m/z 303 [M+H]⁺; 3.72 min (ret time).

D777-((3-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)benzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor D31 starting from 3,4-fluorobenzaldehyde and3-fluoro-5-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 287 [M−H₂O+H]⁺; 1.25 min (ret time).

D78 (2,4-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D31 starting from 2,4-difluorobenzaldehyde.

LCMS (ESI): m/z 127 [M−H₂O+H]⁺; 1.93 min (ret time).

D79 Dideutero(3,5-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D34 starting from methyl 3,5-difluorobenzoate.

LCMS (ESI): m/z 129 [M−H₂O+H]⁺; 2.06 min (ret time)

D83 5-formyl-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D30 starting from 5-(trifluoromethyl)pyridin-3-ol and2-fluoro-5-formylbenzonitrile.

LC-MS (ESI): m/z 293 [M+H]⁺; 1.64 min (ret time).

D815-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D31 starting from5-formyl-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile.

LC-MS (ESI): m/z 293 [M−H]⁻; 1.23 min (ret time).

D82 1,1-dideutero2-amino-2-methylpropan-1-ol

The title compound was prepared by a procedure similar to that describedfor D25 starting from 2-amino-2-methylpropanoic acid and LiAlD₄.

¹H NMR (400 MHz, CDCl₃): δ: 1.98 (s, 2H), 1.28 (s, 3H), 1.10 (s, 3H).

D83 tert-butyl(1,1-dideutero1-hydroxy-2-methylpropan-2-yl)carbamate

The title compound was prepared by a procedure similar to that describedfor D26 starting from 2-amino-1,1-dideutero-2-methylpropan-1-ol andBoc₂O.

D84 1,1-dideutero-2-methyl-2-(methylamino)propan-1-ol

The title compound was prepared by a procedure similar to that describedfor D27 starting from LiAlH₄ andtert-butyl(1,1-dideutero-1-hydroxy-2-methylpropan-2-yl)carbamate.

D851,1-dideutero-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropan-1-ol

The title compound was prepared by a procedure similar to that describedfor D28 starting from 2,4,6-trichloropyrimidine and1,1-dideutero-2-methyl-2-(methylamino)propan-1-ol.

LC-MS (ESI): m/z 252 [M+H]⁺; 1.08 min (ret time).

D861,1-dideutero-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropylmethanesulfonate

The title compound was prepared by a procedure similar to that describedfor D29 starting from 1,1-dideutero-2-methyl-2-(methylamino)propan-1-ol,triethylamine and methanesulfonyl chloride.

D877-chloro-1,2,2-trimethyl-3,3-dideutero-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor D30 starting1,1-dideutero-2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropylmethanesulfonate.

LC-MS (ESI): m/z 216 [M+H]⁺; 0.83 min (ret time).

EXAMPLES E15-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-(3-fluoro-5-(trifluoromethyl)phenoxy)benzonitrile

To a solution of7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30mg, 0.15 mmol) and2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)be-nzonitrile(47 mg, 0.15 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added NaH(12 mg, 0.30 mmol). The reaction mixture was stirred at rt for 30 min.,then quenched with water. Purification via mass-directed autopreparationafforded the title product with trifluoroacetic acid salt as a whitesolid.

LCMS (ESI): 475 [M+H]⁺; 2.83 min (ret time)

E27-((3,4-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and(3,4-dif-luorophenyl)methanol.

LCMS (ESI): m/z 308 [M+H]⁺; 2.03 min (ret time)

E34-(4-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorophenoxy)-2-(trifluoromethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile.

LCMS (ESI): m/z 475 [M+H]⁺; 2.78 min (ret time)

E43-(((2,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

To a solution of7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one(200 mg, 0.720 mmol) and 3-(hydroxymethyl)benzonitrile (288 mg, 2.16mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K₂CO₃ (299 mg,2.16 mmol). The reaction mixture was sealed in a microwave vial andirradiated with a microwave using initial normal to 100° C. for 1 h.Purification via mass-directed auto-preparation afforded the titleproduct as a white solid.

LCMS (ESI): m/z 297 [M+H]⁺; 2.24 min (ret time)

E57-((2,4-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (2,4-difluorophenyl)methanol and7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 308 [M+H]⁺; 0.99 min (ret time).

E6(S)-7-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(s)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.

LCMS (ESI): m/z 451[M+H]⁺; 2.71 min (ret time).

E7(S)-7-((3,4-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,4-difluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 308 [M+H]⁺; 0.96 min (ret time).

E81,2,2-trimethyl-7-(2-(thiophen-2-yl)ethoxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand 2-(thiophen-2-yl)ethanol.

LCMS (ESI): m/z 306 [M+H]⁺; 2.36 min (ret time)

E9(S)-7-((3,4-difluorobenzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of (3,4-difluorophenyl)methanol (45.4 mg, 0.315 mmol) intetrahydrofuran (THF) (3 mL) was added dropwise sodium hydride (37.8 mg,0.945 mmol) at 0° C. After 30 min, (S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate(90 mg, 0.32 mmol) was added. The reaction mixture was stirred at roomtemperature for 16 h, then concentrated. Purification via pre-TLC (ethylacetate) afforded the title product.

LC-MS (ESI): m/z 294 [M+H]⁺; 1.26 min (ret time).

E10(S)-7-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LCMS (ESI): m/z 451[M+H]⁺; 3.03 min (ret time).

E117-((3-chloro-4-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-chloro-4-fluorophenyl)methanol.

LCMS (ESI): m/z 338 [M+H]⁺; 2.36 min (ret time)

E127-((4-((6-chloropyridin-3-yl)oxy)-3-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): m/z 431 [M+H]⁺; 1.01 min (ret time)

E137-((4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((6-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): m/z 449 [M+H]⁺; 1.04 min (ret time)

E14(S)-7-(dideutero(2,3-difluorobenzyl)oxy)-1-isopropyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-7-chloro-1-isopropyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)dideuteromethanol.

LCMS (ESI): m/z 338 [M+H]⁺; 2.37 min (ret time)

E157-(dideutero(2,3-difluorobenzyl)oxy)-1-trideuteromethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-2,2-dimethyl-1-(trideuteromethyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)dideuteromethanol.

LCMS (ESI): m/z 327 [M+H]⁺; 2.16 min (ret time)

E16(S)-7-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland (S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 455 [M+1]⁺; 1.91 min (ret time).

E177-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol and7-chloro-1-cyclopropyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 478 [M+H]⁺; 1.82 min (ret time).

¹H NMR (400 MHz, MeOD) δ 7.59 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H),7.36 (d, J=2.9 Hz, 1H), 7.21 (dd, J=8.8, 2.8 Hz, 1H), 7.08 (d, J=8.6 Hz,2H), 5.41 (s, 1H), 5.35 (s, 2H), 4.02 (t, J=8.7 Hz, 2H), 3.76 (t, J=8.7Hz, 2H), 2.65-2.53 (m, 1H), 0.88-0.75 (m, 4H).

E185-(((1-cyclopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile and7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 469 [M+H]⁻; 1.92 min (ret time)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.0 Hz, 1H), 7.61-7.44 (m, 3H),7.33 (s, 1H), 7.27 (s, 1H), 6.90 (d, J=8.6 Hz, 1H), 5.39 (s, 2H), 5.30(s, 1H), 4.07 (t, J=8.6 Hz, 2H), 3.68 (dd, J=10.3, 6.9 Hz, 2H),2.56-2.42 (m, 1H), 0.90-0.72 (m, 4H).

E19(S)-4-(4-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)ox-y)methyl)-2-fluorophenoxy)-2-(trifluoromethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrileand(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 475 [M+H]⁺; 1.06 min (ret time).

E20(S)-1,2-dimethyl-7-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 326 [M+H]⁺; 2.62 min (ret time)

E217-((3-chlorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-chlorophenyl)methanol.

LCMS (ESI): m/z 320 [M+H]⁺; 2.29 min (ret time).

E22(S)-7-(dideutero(3,4-difluorophenyl)methoxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from dideutero (3,4-difluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 310 [M+H]⁺; 1.03 min (ret time).

E23(S)-7-((4-((5-chloropyridin-3-yl)oxy)-3-fluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 209 [M+H]⁺; 0.96 min (ret time).

E24(S)-5-(4-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)ox-y)methyl)-2-fluorophenoxy)nicotinonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from5-(2-fluoro-4-(hydroxymethyl)phenoxy)nicotinonitrile and(S)-7-chloro-1,2-dimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 408 [M+H]⁺; 0.88 min (ret time).

E257-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 400 [M+H]⁺; 1.99 min (ret time).

E267-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 465 [M+H]⁺; 1.03 min (ret time).

E27(S)-7-((3-fluoro-4-(3-fluorophenoxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 400 [M+H]⁺; 1.99 min (ret time).

E28(S)-7-((3-fluoro-4-(3-fluorophenoxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and(S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 386 [M+H]⁺; 1.91 min (ret time).

E297-((3-fluoro-4-((2-fluoropyridin-4-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimeth-yl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 415 [M+H]⁺; 0.96 min (ret time).

E307-((4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol and7-chloro-1,2,2-tri-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 449 [M+H]⁺; 1.02 min (ret time).

E317-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and(3-fluo-ro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl).

LC-MS (ESI): m/z 451 [M+H]⁺; 2.53 min (ret time).

E323-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and3-(hydroxylmethyl)benzonitrile.

LCMS (ESI): m/z 297 [M+H]⁺; 1.79 min (ret time)

E33(R)-3-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-(hydroxymethyl)benzonitrile and(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 297 [M+H]⁺; 1.09 min (ret time).

E347-((3,5-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,5-difluorophenyl)methanol and7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 308 [M+H]⁺; 1.01 min (ret time).

E35(S)-3-fluoro-5-(((2-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and(S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 301 [M+H]⁺; 1.17 min (ret time).

E367-((4-chloro-3-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (4-chloro-3-fluorophenyl)methanol.

LCMS (ESI): m/z 338 [M+H]⁺; 2.34 min (ret time)

E377-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol andtert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 451 [M+H]⁺; 0.99 min (ret time).

E387-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol andtert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 451 [M+H]⁺; 0.98 min (ret time).

E397-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of tert-butyl7-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate(95 mg, 0.167 mmol) in tetrahydrofuran (THF) (2 mL) stirred at 0° C. wasadded NaH (20.05 mg, 0.501 mmol). The reaction mixture was stirred for18 h at 20° C., quenched with water and concentrated in vacuo.Purification via preparative TLC with ethyl acetate afforded the titleproduct.

LC-MS (ESI): m/z 469 [M+H]⁺; 1.03 min (ret time).

E40(S)-7-((3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-1,2-dimethyl2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 452 [M+H]⁺; 1.20 min (ret time).

E417-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol andtert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 451 [M+H]⁺; 0.98 min (ret time).

E422-fluoro-5-(((1,2,2-trimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and7-chloro-1,2,2-trimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 329 [M+H]⁺; 1.06 min (ret time).

E437-((3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 466 [M+H]⁺; 1.03 min (ret time).

E447-((4-((6-chloropyridin-3-yl)oxy)-3-fluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and tert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 417 [M+H]⁺; 1.81 min (ret time).

E457-((4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol andtert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 435 [M+H]⁺; 1.81 min (ret time).

E467-((2,3-difluorobenzyl)oxy)-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 350 [M+H]⁺; 2.55 min (ret time).

E477-((3-chloro-4-fluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3-chloro-4-fluorophenyl)methanol and7-chloro-1,2-dimethyl-2,3-dihydro imidazo[1,2-c]pyrimidin5(1H)-one.

LC-MS (ESI): m/z 324 [M+H]⁺; 1.50 min (ret time).

E48(R)-1,2-dimethyl-7-((3,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3,4,5-trifluorophenyl)methanol and(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

LC-MS (ESI): m/z 326 [M+H]⁺; 0.77 min (ret time).

E49(S)-2-methyl-7-((3,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3,4,5-trifluorophenyl)methanol and (S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 312 [M+H]⁺; 1.03 min (ret time).

E502,2-dimethyl-7-((3,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one(180 mg, 0.648 mmol) and (3,4,5-trifluorophenyl)methanol (210 mg, 1.30mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K₂CO₃ (269 mg,1.94 mmol). The reaction mixture was sealed in a microwave vial andirradiated with a microwave using initial normal to 100° C. for 1 h.Purification via MDAP afforded the title product as a white solid.

LCMS (ESI): m/z 326 [M+H]⁺; 3.39 min (ret time).

E51(R)-7-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LCMS (ESI): m/z 451 [M+H]⁺; 3.23 min (ret time).

E527-(2-cyclopentylethoxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand 2-cyclopentylethanol.

LCMS (ESI): m/z 292 [M+H⁺; 2.42 min (ret time).

E53(R)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand 2-fluoro-5-(hydroxymethyl).

LC-MS (ESI): m/z 315 [M+H]⁺; 1.00 min (ret time).

E54(S)-7-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and(S)-7-chlo-ro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 226 [M+H]⁺; 1.20 min (ret time).

E55(S)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrileand(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 458 [M+H]⁺; 1.17 min (ret time).

E56(S)-7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 469 [M+H]⁺; 1.24 min (ret time).

E57(S)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-(4-fluorophenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-(4-fluorophenoxy)-5-(hydroxymethyl)benzonitrileand(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 407 [M+H]⁺; 1.03 min (ret time).

E58(S)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 470 [M+H]⁺; 1.02 min (ret time).

E597-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 465 [M+H]⁺; 1.02 min (ret time).

E607-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 483 [M+H]⁺; 1.07 min (ret time).

E617-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 483 [M+H]⁺; 1.05 min (ret time).

E62(S)-7-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and(S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 437 [M+H]⁺; 1.85 min (ret time).

E637-((4-((5-chloropyridin-3-yl)oxy)-3-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 431 [M+H]⁺; 1.01 min (ret time).

E647-((3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 433 [M+H]⁺; 1.00 min (ret time).

E657-((4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl) and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 431 [M+H]⁺; 0.97 min (ret time).

E667-((2,3-difluorobenzyl)oxy)-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 336 [M+H]⁺; 2.33 min (ret time).

E677-(dideutero(2,3-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(5,6-difluoro-4-methylcyclohexa-1,2,3,5-tetraen-1-yl)dideuteromethanoland7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): 324 [M+H]⁺; 2.14 min (ret time)

E687-((3-fluoro-4-((2-fluoropyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and tert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 401 [M+H]⁺; 1.70 min (ret time).

E697-((3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of tert-butyl7-((3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate(130 mg, 0.260 mmol) in dichloromethane (DCM) (4 mL) was added TFA (1.00mL, 13.0 mmol) at 25° C. The reaction mixture was stirred at 25° C.overnight, concentrated and diluted with ethyl acetate/saturated sodiumbicarbonate solution. Organic layer was separated, washed with waterthen saturated brine, dried over sodium sulphate. Purification viapreparative TLC (DCM/MeOH=10/1) afforded the desired product as a whitesolid.

LC-MS (ESI): m/z 401 [M+H]⁺; 1.73 min (ret time).

E703-(((1-cyclopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-(hydroxymethyl)benzonitrile and7-chloro-1-cyclopropyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 309 [M+H]⁺; 1.52 min (ret time)

E715-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile.

LC-MS (ESI): m/z 457 [M+H]⁺; 2.75 min (ret time).

E72(S)-3-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-(hydroxymethyl)benzonitrile and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 297 [M+H]⁺; 1.09 min (ret time).

E73(S)-7-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2-dimethyl-1-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 469 [M+H]⁺; 3.73 min (ret time).

E74(S)-2-fluoro-5-(((2-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and(S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 301 [M+H]⁺; 0.99 min (ret time).

E75(S)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and(S)-7-chloro-1,2-dimethyl-2,3-dihydro-oimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 315 [M+H]⁺; 1.00 min (ret time).

E76(S)-7-((3,5-difluoro-4-(3-fluorophenoxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,5-difluoro-4-(3-fluorophenoxy)phenyl)methanoland(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 419 [M+H]⁺; 1.04 min (ret time).

E777-((2,4-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (2,4-difluorophenyl) and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrim-idin-5(1H)-one

LC-MS (ESI): m/z 322 [M+H]⁺; 2.32 min (ret time).

E78(S)-7-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and(S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 437 [M+H]⁺; 1.79 min (ret time).

E791,2,2-trimethyl-7-(dideutero(2,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (2,4,5-trifluorophenyl)methanol, deuteride and7-chloro-1,2,2-trimethyl-2,3-dihydro-oimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 342 [M+H]⁺; 2.14 min (ret time).

E807-(2,3-difluorophenethoxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-(2,3-difluorophenyl)ethanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 336 [M+H]⁺; 0.89 min (ret time).

E81(S)-7-(dideutero(2,3-difluorobenzyl)oxy)-1-ethyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(S)-7-chloro-1-ethyl-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)dideuteromethanol.

LCMS (ESI): m/z 324 [M+H]⁺; 2.21 min (ret time).

E827-((4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol andtert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 417 [M+H]⁺; 1.76 min (ret time).

E831-cyclopropyl-7-((3,4-difluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,4-difluorophenyl)methanol and7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 320 [M+H]⁺; 1.61 min (ret time)

E843-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-5-fluorobenzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and7-chloro-1,2-dimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 316 [M+H]⁺; 1.28 min (ret time).

E85(S)-7-((3,5-difluorobenzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,5-difluorophenyl)methanol and(S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 294 [M+H]⁺; 0.79 min (ret time).

E86(S)-7-(dideutero(3,4,5-trifluorophenyl)methoxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from dideutero (3,4,5-trifluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 328 [M+H]⁺; 1.08 min (ret time).

E877-(2-(5-chlorothiophen-2-yl)ethoxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one(90.0 mg, 0.421 mmol) and 2-(5-chlorothiophen-2-yl)ethanol (68.5 mg,0.421 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added Cs₂CO₃ (274mg, 0.842 mmol). The reaction mixture was stirred at 130° C. for 5 h,quenched with water. Purification via MDAP afforded the title product asa white solid.

LCMS (ESI): m/z 340 [M+H]⁺; 2.37 min (ret time).

E88(S)-2-(3,4-difluorophenoxy)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 425 [M+H]⁺; 1.00 min (ret time).

E89(S)-2-chloro-5-(4-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorophenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from2-chloro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 441 [M+H]⁺; 1.03 min (ret time).

E907-((4-((5-chloropyridin-3-yl)oxy)-3-fluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol andtert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 417 [M+H]⁺; 0.94 min (ret time).

E917-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanolandtert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyramidine-1(5H)-carbo-xylate.

LC-MS (ESI): m/z 469 [M+H]⁺; 1.01 min (ret time).

E927-((2,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (2,5-difluorophenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 322 [M+H]⁺; 2.31 min (ret time).

E937-(dideutero(3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from of7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,5-dideuterophenyl)difluoromethanol.

LCMS (ESI): m/z 324 [M+H]⁺; 2.22 min (ret time).

E94(S)-7-((3-fluoro-4-(4-fluorophenoxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3-fluoro-4-(4-fluorophenoxy)phenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 400 [M+H]⁺; 1.98 min (ret time).

E957-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanoland7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one at−78° C. then rt.

LC-MS (ESI): m/z 484 [M+H]⁺; 1.05 min (ret time).

E967-((3,5-difluorobenzyl)oxy)-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 350 [M+H]⁺; 2.53 min (ret time).

E977-(dideutero(3,5-difluorobenzyl)oxy)-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,5-dideuterophenyl)difluoromethanol.

LCMS (ESI): m/z 352 [M+H]⁺; 2.53 min (ret time)

E987-((3-fluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3-fluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl) and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): m/z 415 [M+H]⁺; 0.97 min (ret time)

E997-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo-[1,2c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (4-fluoro-3-(trifluoromethyl)phenyl)methanol, NaHand7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-onefrom −78° C. to rt.

LC-MS (ESI): m/z 372 [M+H]⁺; 0.97 min (ret time).

E1007-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanoland tert-butyl,7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carbox-ylate.

LC-MS (ESI): m/z 470 [M+H]⁺; 1.02 min (ret time).

E1017-((3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol andtert-buty-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 452 [M+H]⁺; 0.99 min (ret time).

E1027-(dideutero(2,3-difluorobenzyl)oxy)-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyri-midin-5(1H)-oneand (2,3-difluorophenyl)dideuteromethanol.

LCMS (ESI): m/z 338 [M+H]⁺; 2.33 min (ret time).

E1037-((2,3-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3difluorophenyl)methanol.

LCMS (ESI): m/z 322 [M+H]⁺; 2.19 min (ret time).

E1047-((2,3-difluorobenzyl)oxy)-1-trideuteromethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-2,2-dimethyl-1-(trideuteromethyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 325 [M+H]⁺; 2.18 min (ret time).

E1057-(dideutero(2,3-difluorobenzyl)oxy)-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)dideuteromethanol

LCMS (ESI): m/z 352 [M+H]⁺; 2.50 min (ret time).

E106(R)-7-((3,4-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,4-difluorophenyl)methanol and(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 308 [M+H]⁺; 0.97 min (ret time).

E107(R)-7-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.

LCMS (ESI): m/z 451 [M+H]⁺; 2.70 min (ret time)

E108(S)-1,2-dimethyl-7-((3,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3,4,5-trifluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 326 [M+H]⁺; 0.81 min (ret time).

E109(S)-3-(((2-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-(hydroxymethyl)benzonitrile and (S)-tert-butyl7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 283 [M+H]⁺; 0.92 min (ret time).

E1101,2,2-trimethyl-7-((3,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 340 [M+H]⁺; 2.64 min (ret time).

E111(S)-7-((2,3-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 308 [M+H]⁺; 2.44 min (ret time).

E1127-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): m/z 465 [M+H]⁺; 1.06 min (ret time)

E1137-((4-((5-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-((5-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LCMS (ESI): m/z 449 [M+H]⁺; 1.03 min (ret time)

E1147-((3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 322 [M+H]⁺; 2.87 min (ret time).

E1151,2,2-trimethyl-7-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 340 [M+H]⁺; 3.04 min (ret time)

E1167-((3,5-difluoro-4-((2-fluoropyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol andtert-butyl7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 419 [M+H]⁺; 1.76 min (ret time).

E1177-(3,4-difluorophenethoxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-(3,4-difluorophenyl)ethanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 336 [M+H]⁺; 1.11 min (ret time).

E1185-(((1-cyclopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-(3,4-difluorophenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 437 [M+H]⁺; 1.65 min (ret time)

E1197-((3-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and(3-fluo-ro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)phenyl)methanol.

LCMS (ESI): m/z 468 [M+H]⁺; 3.02 min (ret time).

E1207-((3,4-difluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

To a solution of7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one(200 mg, 0.720 mmol) and (3,4-difluorophenyl)methanol (311 mg, 2.160mmol) in N,N-dimethylformamide (DMF) (3.5 ml) was added K₂CO₃ (299 mg,2.160 mmol). The reaction mixture was sealed in a microwave vial andirradiated with a microwave using initial normal to 100° C. for 1 h.Purification via MDAP afforded the title product with trifluoroaceticacid salt (16 mg) as a white solid.

LCMS (ESI): m/z 308 [M+H]⁺; 2.71 min (ret time).

E1215-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and7-chloro-1,2-dimethyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 315 [M+H]⁺; 2.20 min (ret time).

E1227-((3,4-difluorobenzyl)oxy)-1,2,2-trimethyl-2-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,4-difluorophenyl)methanol.

LCMS (ESI): m/z 322 [M+H]⁺; 2.26 min (ret time).

E123(R)-5-(((1,2-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile.

LCMS (ESI): m/z 458 [M+H]⁺; 2.42 min (ret time).

E1243-(((1,2,2-trimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E9 starting from 3-(hydroxymethyl)benzonitrile and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 311 [M+H]⁺; 1.92 min (ret time).

E1257-((3-chloro-5-fluorobenzyl)oxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3-chloro-5-fluorophenyl)methanol.

LCMS (ESI): m/z 338 [M+H]⁺; 2.39 min (ret time).

E126(S)-7-((4-(3,4-difluorophenoxy)-3,5-difluorobenzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol and(S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 437 [M+H]⁺; 1.06 min (ret time).

E1277-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanolandtert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 469 [M+H]⁺; 1.01 min (ret time).

E1287-((4-((5-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E39 starting fromtert-butyl-7-((4-((5-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 435 [M+H]⁺; 0.97 min (ret time).

E1297-((3,5-difluorobenzyl)oxy)-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 336 [M+H]⁺; 3.65 min (ret time).

E130(S)-7-((3-fluoro-4-(4-fluorophenoxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from (3-fluoro-4-(4-fluorophenoxy)phenyl)methanol and(S)-tert-butyl-7-chloro-2-meth-yl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 386 [M+H]⁺; 1.90 min (ret time).

E131(S)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland(S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 455 [M+H]⁺; 1.85 min (ret time).

E1327-(3,5-difluorophenethoxy)-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E9 starting from 2-(3,5-difluorophenyl)ethanol and7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.

LC-MS (ESI): m/z 336 [M+H]⁺; 0.67 min (ret time).

E1337-((4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E69 starting from tert-butyl7-((4-((6-chloropyridin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 435 [M+H]⁺; 1.86 min (ret time).

E1347-((3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E69 starting from tert-butyl7-((3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

LC-MS (ESI): m/z 419 [M+H]⁺; 1.78 min (ret time).

E1357-((2,4-difluorobenzyl)oxy)-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4-difluorophenyl)methanol.

LCMS (ESI): m/z 350 [M+H]⁺; 2.48 min (ret time).

E1367-((2,3-difluorobenzyl)oxy)-1,2,2-trimethyl-3,3-dideutero-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-3,3-dideutero-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one,(2,3-difluorophenyl)methanol and sodium hydride.

LCMS (ESI): m/z 324 [M+H]⁺; 2.09 min (ret time)

E1377-((3,5-difluorobenzyl)oxy)-1,2,2-trimethyl-3,3-dideutero-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from7-chloro-3,3-dideutero-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one,(2,3-difluorophenyl)methanol and sodium hydride.

LCMS (ESI): m/z 324 [M+H]⁺; 2.13 min (ret time)

D. Biological Assays and Data

The compounds of present invention are Lp-PLA₂ inhibitors, and areuseful in the treatment of diseases mediated by Lp-PLA₂. The biologicalactivities of the compounds of present invention can be determined byusing any suitable assay for determining the activity of a compound as aLp-PLA₂ inhibitor, as well as tissue and in vivo models.

The biological activity data for each compound was either reported in atleast one experiment or the average of multiple experiments. It isunderstood that the data described herein may have reasonable variationsdepending on the specific conditions and procedures used by the personconducting the experiments.

Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Biochemical Assay

(1) Recombinant Human Lp-PLA₂ Assay (rhLp-PLA₂) (Also Referred to as“PED6” Assay)

N-((6-(2,4-dinitrophenyl)amino)-hexanoyl)-2-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-1-hexadecanoyl-sn-glycero-3-phosphoethanolamine,triethylammonium salt (PED6) is a commercially availablefluorescently-labeled phospholipid, which is commercially available fromInvitrogene and Molecular Probes. There is a quenching para-nitro phenyl(PNP) group in the sn3 position and a Bodipy fluorescein (FL) group inthe sn2 position. Upon cleavage with Lp-PLA₂, the Bodipy FL group isliberated and then may result in an increase in fluorescence. Inhibitorsof Lp-PLA₂ therefore prevent this cleavage and no fluorescent increaseis observed.

The PED6 assay was run as an unquenched 10 μL assay. The source platecontaining the compounds to be tested was prepared by making 1:3 (byvolume) serial dilution of the compounds within DMSO on 384-wellmicroplate. Then, 0.01 μL of the compounds on compound source plate weretransferred into 384 well Greiner 784076 (black) plates using ECHOliquid dispenser. 5 μL of recombinant human Lp-PLA₂ enzyme (4 nM (or 110μM) rhLp-PLA₂ in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mMCHAPS) was added to each well of the plate. Plates were centrifuged for10 sec at 500 rpm. After 30 minutes preincubation, 5 μL of substrate (4M (or 5 M) PED6 [from 5 mM DMSO stock] in assay buffer of 50 mM HEPES,pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to 384 well Greiner 784076(black) plates. Plates were centrifuged for 10 sec at 500 rpm. The platewas covered to protect it from light and incubated for 20 min at roomtemperature. The plates were read for fluorescence intensity at ex:480/em: 540 using ViewLux microplate imager for Envisionspectrofluoroimeters pIC50 data, curve and QC analysis was conducted byusing XL fit module in Excel.

All exemplified compounds of the present invention were tested accordingto the PED6 assay described above or similar assays and were found todemonstrate inhibition activity to Lp-PLA₂. The plC₅₀ value for allexemplified compounds in PED6 assay was either reported in at least oneexperiment or the average of multiple experiments.

The plC₅₀ values in the PED6 assay for all exemplified compounds were atleast 6.0.

The plC₅₀ values in the PED6 assay for examples 1-3, 6-13, 15-19, 21-31,36-46, 48-51, 53-69, 71, 73-78, 82, 86, 88-98, 100-108, 110, 112-114,116, 118, 119, 121-131, 133, 134, 136 and 137 were at least 8.0.

The plC₅₀ values in the PED6 assay for examples 1, 3, 6, 10-13, 16, 18,19, 23, 25, 26, 29-31, 37-39, 41-45, 50, 51, 54-65, 68, 69, 71, 73, 76,78, 82, 88, 89-91, 95-98, 100, 101, 105, 107, 112-114, 116, 119,122-124, 126-128, 131, 133 and 134 were at least 9.0.

For example, the pIC50 values in the PED6 assay for following examplesare:

Example rhLp-PLA₂ (PED6 assay) No. (pIC50) E12  10.5 E13  10.3 E23  9.8E25  10.1 E26  10.8 E29  9.7 E42  9.5 E43  10.3 E46  8.4 E54  9.9 E56 10.0 E58  10.2 E59  10.4 E60  10.4 E61  9.9 E63  10.0 E64  10.1 E95 10.1 E96  9.5 E97  9.2 E105 9.2 E114 9.1

(2) PLA2 VIIB Assay

PLA2 VIIB (also known as Novel Serine Dependent Lipase, NSDL) is aserine hydrolase with 40% amino acid identity with human Lp-PLA₂.Sequence comparisons indicate that the PLA VIIB active site catalytictriad positions are similar to those of Lp-PLA₂. Similar to Lp-PLA₂, itis capable of hydrolyzing oxidatively modified phospholipids and may beassayed using known Lp-PLA₂ substrates.

Upon cleavage by a phopholipase, PLA2 VIIB liberates a fluorescentBodipy group. Recombinant human PLA2 VIIB is used as the phospholipasesource in this assay, and compounds are screened to test their degree ofinhibition in this assay. The assay is used to determine the degree ofselectivity of the testing compounds between PLA2 VIIB and Lp-PLA₂.

The PLA2 VIIB assay was applied as an unquenched 10 μL assay. The sourceplate containing the compounds is prepared by making 1:3 (by volume)serial dilution of the compounds with pure DMSO on 384-well microplate.0.01 μL of compounds on the compound source plate were transferred into384 well Greiner 784076 (black) plates—by ECHO liquid dispenser. 5 μL ofNovel Serine Dependent Lipase (NSDL) enzyme (5 nM NSDL in assay bufferof 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well.Plates were centrifuged for 10 sec at 500 rpm. After 30 minutespreincubation, 5 μL of substrate (5 M PED6 [from 5 mM DMSO stock] inassay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was addedto 384 well Greiner 784076 (black) low-volume plates. Plates werekinetic read by starting read immediately after PED6 addition at ex:480/em: 540 using ViewLux microplate reader or Envisionspectrofluorimeters. IC 50 data (which may be converted to pIC50 data),curve and QC analysis was conducted using XLfit module in Excel.

All exemplified compounds of the present invention except examples 136and 137 were tested in PLA2 VIIB assay described above or similarassays. All tested examples except examples 5, 35, 99, 111 and 120 hadat least 100 fold selectivity between human recombinant Lp-PLA₂ and PLA2VIIB.

(3) Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Human Plasma Assay(Also Referred to as “Thio-PAF assay”)

The human plasma assay utilizes a thioester analog of PAF(phosphatidylcholine), where hydrolysis yields to the formation of aphospholipid containing a free thiol group. The amount of thiol isquantitated continuously by reacting with CPM(7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin), a maleimidewhich increases in fluoresence after Michael addition of thiols. Thisassay may detect the activity of Lp-PLA₂ in human plasma, as determinedby specific inhibition by Lp-PLA₂ inhibitors.

The thio-PAF assay was run as a quenched 15 μL assay. Compounds sourceplate was prepared by making 1:3 (by volume) serial dilution of thecompounds into pure DMSO on 384-well microplate. 0.01 μL of compounds oncompound source plate were transferred to 384 well Greiner 784076(black) low-volume plates by ECHO liquid dispenser. 8 μL pooled humanplasma, which was previously aliquoted and frozen, was added. Plateswere centrifuged for 10 sec at 500 rpm. After 30 minutes preincubation,2 μL of substrate solution comprising 2.5 mM 2-thio-PAF [from ethanolstock], 32 μM CPM [from a DMSO stock] and 3.2 mM NEM (N-ethylmaleimide)[made fresh daily in DMSO] in assay buffer of 50 mM HEPES, pH 7.4, 150mM NaCl, 1 mM CHAPS was added to 384 well Greiner 784076 (black)low-volume plates by BRAVO liquid handling station. After 2 mins,reaction was quenched with 5 μL of 5% aqueous trifluoroacetic acid(TFA). Plates were covered to protect from light and incubated for 40min at room temperature. Plates were read at ex: 380/em: 485using-Envision microplate reader. PIC50 data, curve and QC analysis wereconducted by using XLFit module in Excel.

All exemplified compounds of the present invention were tested inthio-PAF assay described above or similar assays.

The pIC₅₀ values in the thio-PAF assay for all compounds except examples111 and 120 were at least 5.0.

The plC₅₀ values in the thio-PAF assay for examples 1-3, 7, 8, 10-13,15, 16, 18, 19, 23, 25, 26, 29-31, 33, 37-46, 48-56, 58-61, 63-69,71-75, 77, 78, 82, 85, 88-91, 93, 95-98, 100-110, 112-117, 119, 121-124,127-129, 131, 133, 134, 136 and 137 were at least 7.0.

E. Methods of Use

The compounds of this invention are inhibitors of Lp-PLA₂. Therefore,these compounds may be used in therapy, for example, in the treatment ofdisorders associated with the activity of Lp-PLA₂. Accordingly, anotheraspect of the invention is directed to methods of treating conditionsassociated with the activity of Lp-PLA₂. As will be appreciated by thoseskilled in the art, a particular condition or its treatment may involveone or more underlying mechanisms associated with Lp-PLA₂ activity,including one or more of the mechanisms described herein.

In some embodiments, an inhibitor of Lp-PLA₂ according to the inventionmay be used in treating any of the disorders disclosed in the followingpublished patent applications: WO96/13484, WO96/19451, WO97/02242,WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099, WO99/24420,WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904,WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179,WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048,867, US2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048,866,WO05/003118 CA 2530816A1), WO6/063811, WO06/063813, WO 2008/141176, JP200188847, US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829A1.

In certain embodiments, the compounds of this invention may be used totreat any diseases that involve endothelial dysfunction, for example,atherosclerosis, (e.g. peripheral vascular atherosclerosis andcerebrovascular atherosclerosis), diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In certain embodiments, the compounds of the present invention may beused to treat any disease that involves lipid oxidation in conjunctionwith enzyme activity, for example, in addition to conditions such asatherosclerosis and diabetes, other conditions such as rheumatoidarthritis, stroke, inflammatory conditions of the brain such asAlzheimer's Disease, various neuropsychiatric disorders such asschizophrenia, myocardial infarction, ischaemia, reperfusion injury,sepsis, and acute and chronic inflammation.

In certain embodiments, the compounds of the present invention may beused to treat diseases that involve activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂ includingdiseases involving activated macrophages such as M1, dendritic and/orother macrophages which generate oxidative stress; exemplary disorderincludes, but are not limited to, psoriasis, rheumatoid arthritis, woundhealing, chronic obstructive pulmonary disease (COPD), liver cirrhosis,atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronicgastritis, aortic aneurysm, atherosclerosis, multiple sclerosis,Alzheimer's disease, and autoimmune diseases such as lupus.

In certain embodiments, the present invention provides methods oftreating a disease associated with the activity of Lp-PLA₂, whichcomprises treating a subject in need thereof with a therapeuticallyeffective amount of an inhibitor of Lp-PLA₂. The disease may beassociated with the increased involvement of monocytes, macrophages orlymphocytes; with the formation of lysophosphatidylcholine and oxidizedfree fatty acids; with lipid oxidation in conjunction with Lp-PLA₂activity; or with endothelial dysfunction.

In other embodiments, the compounds of the invention may be used for theprimary or secondary prevention of acute coronary events, e.g. caused byatherosclerosis; adjunctive therapy in the prevention of restenosis; ordelaying the progression of diabetic or hypertensive renalinsufficiency. Prevention includes treating a subject at risk of havingsuch conditions.

In certain embodiment, the compounds of the present invention may beused to treat the disease described herein in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLipoprotein (a) (Lp(a)). Examples of the above include, but are notlimited to, cholesterol synthesis inhibitors such as statins,anti-oxidants such as probucol, insulin sensitizers, calcium channelantagonists, and anti-inflammatory drugs such as non-steroidalanti-inflammatory Drugs (NSAIDs). Examples of agents for lowering Lp(a)include the aminophosphonates described in WO 97/02037, WO 98/28310, WO98/28311 and WO 98/28312.

In one embodiment, the compounds of the present invention may be usedwith one or more statins. The statins are a well-known class ofcholesterol lowering agents and include atorvastatin, simvarstatin,pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin. Thetwo agents may be administered at substantially the same time or atdifferent times, according to the discretion of the physician.

In a certain embodiment, the compounds of the present invention may beused with an anti-diabetic agent or an insulin sensitizer. In oneembodiment, a compound of the present invention may be used with PPARgamma activators, for instance GI262570 (GlaxoSmithKline) and theglitazone class of compounds such as rosiglitazone, troglitazone andpioglitazone.

In one embodiment, the compounds of the present invention may be used totreat a neurodegeneration disease in a subject. The methods compriseadministering to a subject in need thereof a pharmaceutical compositioncomprising an agent that inhibits the activity of Lp-PLA₂. Exemplaryneurodegeneration diseases include, but are not limited to, Alzheimer'sdisease, vascular dementia, Parkinson's disease and Huntington'sdisease. In a certain embodiment, the neurodegeneration diseasedescribed herein is associated with an abnormal blood brain barrier. Inone embodiment, the subject which is administered an agent that inhibitsthe activity of Lp-PLA₂ is a human.

In one embodiment, the present invention provides methods of treating asubject with or at risk of vascular dementia. The methods compriseadministering to the subject a pharmaceutical composition comprising asafe and effective amount of a compound of the present invention. In acertain embodiment, the vascular dementia is associated with Alzheimer'sdisease.

In certain embodiments, the present invention provides methods oftreating a neurological disorder associated with an abnormal blood brainbarrier (BBB) function, inflammation, and/or microglia activation in asubject in need thereof. The methods comprise administering to thesubject a safe and effective amount of a compound of the presentinvention. In a further embodiment, the abnormal BBB is a permeable BBB.In yet a further embodiment, the disease is a neurodegeneration disease.Such neurodegeneration diseases are, for example, but are not limitedto, vascular dementia, Alzheimer's disease, Parkinson's disease andHuntington's disease. In one embodiment, the present invention providesmethods of treating disease associated with a subject with blood brainbarrier (BBB) leakage. Exemplary diseases include, but are not limitedto, brain hemorrhage, cerebral amyloid angiopathy. In one embodiment,the neurodegeneration disease is Alzheimer's disease. In a certainembodiment, the neurodegeneration disease is vascular dementia. In oneembodiment, the neurodegeneration disease is multiple sclerosis (MS).

In certain embodiments, the present invention provides methods ofdecreasing beta amyloid, referred to as “Aβ” accumulation in the brainof a subject. The methods comprise administering to a subject in needthereof a pharmaceutical composition comprising a safe and effectiveamount of a compound of the present invention. In a further embodiment,the beta amyloid is Abeta-42.

In certain embodiments, when a subject is administered a safe andeffective amount of a compound of the present invention, the methods mayfurther comprise administering to the subject another therapeutic agentthat may be useful in treating the neurodegenerative disease for whichthe subject is being treated, or that may be a co-morbidity. Forexample, when the neurodegenerative disease is similar to Alzheimer'sdisease, the subject may be treated with other agents targetingAlzheimer's disease such as ARICEPT® or donepezil, COGNEX® or tacrine,EXELON® or rivastigmine, REMINYL® or galantamine, anti-amyloid vaccine,Abeta-lowering therapies, mental exercise or stimulation.

In certain embodiments, the present invention relates to methods oftreating metabolic bone diseases by administering to the subject in needthereof a safe and effective amount of a compound of the presentinvention. Exemplary metabolic bone diseases include, diseasesassociated with loss of bone mass and density including, but are notlimited to, osteoporosis and osteopenic related diseases. Exemplaryosteoporosis and osteopenic related diseases include, but are notlimited to, bone marrow abnormalities, dyslipidemia, Paget's diseases,type II diseases, metabolic syndrome, insulin resistance,hyperparathyroidism and related diseases. In a further embodiment, thesubject in need thereof is a human.

It is believed that methods of preventing osteoporosis and/or osteopenicdiseases described herein may be affected by inhibiting the expressionof Lp-PLA₂ and/or inhibiting the protein activity of Lp-PLA₂.Accordingly, some embodiments of the present invention provide methodsfor inhibiting Lp-PLA₂ by blocking enzyme activity. In a furtherembodiment, methods for inhibiting Lp-PLA₂ by reducing and/ordown-regulating the expression of Lp-PLA₂ RNA are provided. In a furtherembodiment, preventing and/or reducing loss of bone mass and/or loss ofbone density leads to preventing or reducing symptoms associated withmetabolic bone diseases such as osteoporosis and/or osteopenic diseases.

In certain embodiments, the methods further comprise administering to asubject in need thereof additional therapeutic agents used in thetreatment of metabolic bone diseases. For example, when the metabolicbone disease is osteoporosis additional therapeutic agents such asbisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin,raloxifene, a selective estrogen modulator (SERM), estrogen therapy,hormone replacement therapy (ET/HRT) and teriparatide) may be used.

One aspect of the present invention provides methods for treating eyediseases by administering a safe and effective amount of a compound ofthe present invention. Eye diseases applicable in the present inventionmay be associated with the breakdown of the inner blood-retinal barrier(iBRB). Exemplary eye diseases relate to diabetic eye diseases anddisorders, which includes macular edema, diabetic retinopathy, and thelike. Further, in one embodiment, the present invention relates tomethods for treating eye diseases by administering a compound of thepresent invention to inhibit Lp-PLA₂. Exemplary eye diseases include,but are not limited to, central retinal vein occlusion, branched retinalvein occlusion, Irvine-Gass syndrome (post cataract and post-surgical),retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy,epiretinal membrane, choroidal tumors, cystic macular edema, parafovealtelengiectasis, tractional maculopathies, vitreomacular tractionsyndromes, retinal detachment, neuroretinitis, idiopathic macular edema,and the like.

Further, some embodiments of the present invention provide methods fortreating diabetic macular edema in a subject. The method comprisesadministering to a subject in need thereof a safe and effective amountof a compound of the present invention.

In certain embodiments, the present invention provides methods oftreating a subject with or at risk of macular edema. The methodscomprise administering to the subject a safe and effective amount of acompound of the present invention. In a further embodiment, the macularedema is associated with diabetic eye disease, for example, diabeticretinopathy. In yet a further embodiment, the macular edema isassociated with posterior uveitis.

In certain embodiments, the present invention provides methods oftreating glaucoma or macular degeneration. The methods compriseadministering to the subject a safe and effective amount of a compoundof the present invention.

In one embodiment, the present invention provides methods of treating adisease associated with the breakdown of the inner blood-retinal barrierin a subject in need thereof. The methods comprise administering to thesubject a safe and effective amount of a compound of the presentinvention.

In one embodiment, systemic inflammatory diseases such as, juvenilerheumatoid arthritis, inflammatory bowel disease, Kawasaki disease,multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis,reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Haradasyndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis,chronic granulomatous disease, enthesitis, may be the underlying causeof posterior uveitis affecting the retina, and which can result inmacula edema. The present invention relates to methods for treatingposterior uveitis or any of these systemic inflammatory diseases byadministering a safe and effective amount of a compound of the presentinvention.

It is believed that Lp-PLA₂ inhibitors may have beneficial effects onindications associated with M1/M2 macrophage polarization. The belief isbased on the following studies. A study was carried out by GSK toinvestigate the relationship between M1/M2 macrophage polarization anddifferent diseases. 94 human markers described in Martinez F O et al.,which distinguished M1 and M2 phenotypes was used against a GSKsubscribed GeneLogic database. (See Martinez F O et al. (2006) J Immunol177, 7303-7311.) The Connectivity Map methodology described in Lamb J etal. was used to identify the fraction of samples in each disease statehaving expression characteristics consistent with a M1-favoring orM2-favoring macrophage population. (See Lamb J et al. (2006) Science313, 1929-1935) (PMID 17008526)). The study showed that liver cirrhosis,skin psoriasis, atopic dermatitis, pulmonary emphysema, chronicpancreatitis, chronic gastritis, and aortic aneurysm have M1/M2imbalance.

A further study was carried out to study the impact of Lp-PLA₂inhibitors on modulating M1/M2 imbalance. In this study, rats wereinduced to develop experimental autoimmune encephalomyelitis (EAE) byimmunization with myelin basic protein (MBP) antigen and treated with aknown Lp-PLA₂ inhibitor:5-((9-Methoxy-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-2-yl)oxy)-2-(3-(trifluoromethyl)phenoxy)benzonitrile(See PCT application no. PCT/CN2011/001597). In this preventivetreatment model, the compound was administered at day 0 (day ofimmunization) and continued to administer until day 22. The study lastedfor 25 days. Rats were subsequently monitored for symptoms of EAE. Ratswere immunized with MBP to develop EAE and symptoms were monitoreddaily. Plasma Lp-PLA₂ activity, OxLDL, and LysoPC concentration weredetermined at different time points through the course of EAE. Theresults showed that plasma Lp-PLA₂ activity, OxLDL, and LysoPCconcentrations increased as the clinical EAE disease progressed in themodel, which indicates that they played a role in the pathologydevelopment. Lp-PLA₂ inhibitor treatment led to reduction in clinicaldisease associated with decreased Lp-PLA₂ activity and LysoPC levels inrat EAE plasma. Hence, inhibition of Lp-PLA₂ activity is beneficial inameliorating disease in the rat EAE model.

Ex vivo analysis of proinflammatory (M1) and anti-inflammatory (M2)markers in control and compound treated EAE rats. Splenic macrophageswere harvested at day 13 post MBP-immunization and assayed forexpression of a variety of markers by realtime PCR. CNS infiltratingcells were harvested and macrophages were analyzed for expression of M1and M2 markers by realtime PCR. Treatment with compound resulted in thedecrease in M1 markers and increase in M2 markers, which potentiallyindicated the possibility of anti-inflammation and tissue repair.

Therefore, in certain embodiments, the present invention providesmethods of treating disease associated with macrophage polarization, forexample, M1/M2 macrophage polarization. Exemplary diseases associatedwith macrophage polarization include, but are not limited to, livercirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema,chronic pancreatitis, chronic gastritis, aortic aneurysm,atherosclerosis, multiple sclerosis, amnyotrophic lateral sclerosis(ALS) and other autoimmune diseases that are associated with macrophagepolarization.

One aspect of the present invention provides the use of a compound ofthe present invention for the preparation of a medicament for carryingout a method described herein. Another aspect of the present inventionprovides a compound of the present invention for use in carrying outmethods of treatment described herein. A further aspect of the presentinvention provides a compound described herein or a pharmaceuticallyacceptable salt thereof, for use in therapy.

F. Composition

The compounds of the present invention may be formulated intopharmaceutical compositions prior to administration to a subject.Accordingly, one aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of the invention and one or morepharmaceutically-acceptable excipients. In accordance with anotheraspect of the invention, a process is provided for the preparation of apharmaceutical composition including admixing a compound of the Formula(I) or salts thereof, solvates etc thereof, with one or morepharmaceutically acceptable excipient.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.1 mg, 0.5 mg, or 1 mg to 50 mg,100 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1 g of a compound of thepresent invention, depending on the condition being treated, the routeof administration and the age, weight and condition of the subject, orpharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose. Inother embodiments, the unit dosage compositions are those containing adaily dose or sub-dose as described herein, or an appropriate fractionthereof, of an active ingredient. Furthermore, such pharmaceuticalcompositions may be prepared by any of the methods well-known to oneskilled in the art.

An effective amount of a compound of the present invention will dependupon a number of factors including, for example, the age and weight ofthe intended recipient, the precise condition requiring treatment andits severity, the nature of the formulation, and the route ofadministration, and will ultimately be at the discretion of theattendant prescribing the medication. However, an effective amount of acompound of present invention for the treatment of anemia will generallybe in the range of 0.1 to 100 mg/kg body weight of recipient per day andmore usually in the range of 1 to 10 mg/kg body weight per day. Thus,for a 70 kg adult mammal, the actual amount per day would usually befrom 70 to 700 mg and this amount may be given in a single dose per dayor in a number of sub-doses per day as such as two, three, four, five orsix doses per day. Or the dosing can be done intermittently, such asonce every other day, once a week or once a month. An effective amountof a salt or solvate, etc., may be determined as a proportion of theeffective amount of the compound of Formula (I) per se. It is envisagedthat similar dosages would be appropriate for treatment of the otherconditions referred to above.

The pharmaceutical compositions of the invention may contain one or morecompounds of the invention. In some embodiments, the pharmaceuticalcompositions may contain more than one compound of the invention. Forexample, in some embodiments, the pharmaceutical compositions maycontain two or more compounds of the invention. In addition, thepharmaceutical compositions may optionally further comprise one or moreadditional pharmaceutically active compounds.

As used herein, “pharmaceutically-acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient may be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a subject and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided.

The compounds of the invention and the pharmaceutically-acceptableexcipient or excipients may be formulated into a dosage form adapted foradministration to the subject by the desired route of administration.For example, dosage forms include those adapted for (1) oraladministration (including buccal or sublingual) such as tablets,capsules, caplets, pills, troches, powders, syrups, elixers,suspensions, solutions, emulsions, sachets, and cachets; (2) parenteraladministration (including subcutaneous, intramuscular, intravenous orintradermal) such as sterile solutions, suspensions, and powders forreconstitution; (3) transdermal administration such as transdermalpatches; (4) rectal administration such as suppositories; (5) nasalinhalation such as dry powders, aerosols, suspensions, and solutions;and (6) topical administration (including buccal, sublingual ortransdermal) such as creams, ointments, lotions, solutions, pastes,sprays, foams, and gels. Such compositions may be prepared by anymethods known in the art of pharmacy, for example by bringing intoassociation a compound of Formula (I) with the carrier(s) orexcipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Suitable pharmaceutically-acceptable excipients may vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically-acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate carrying or transporting the compound or compounds of theinvention once administered to the subject from an organ, or a portionof the body, to another organ, or a portion of the body. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchthe excipient is present in the formulation and what other ingredientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically-acceptable excipients and may be useful inselecting suitable pharmaceutically-acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a safe and effective amount of acompound of the invention and a diluent or filler. Suitable diluents andfillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch(e.g. corn starch, potato starch, and pre-gelatinized starch), celluloseand its derivatives (e.g. microcrystalline cellulose), calcium sulfate,and dibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

In certain embodiment, the present invention is directed to apharmaceutical composition comprising 0.01 to 1000 mg of one or morecompounds described herein or a pharmaceutically acceptable salt thereofand 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention is directed apharmaceutical composition for the treatment of neurodegenerationdisease comprising a compound described herein or a pharmaceuticallyacceptable salt thereof.

What is claimed is: 1.(S)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound having a structure of

or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 3. A method for treatingAlzheimer's disease in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound having a structure of

or pharmaceutically acceptable salt thereof.
 4. The method according toclaim 3, wherein the subject is human.
 5. The compound according toclaim 1 is(S)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one


6. The compound according to claim 1 is a pharmaceutically acceptablesalt of(S)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one